Abstract:
To gain a better understanding of tumor angiogenesis, new techniques for isolating endothelial cells (ECs) and evaluating gene expression patterns were developed. When transcripts from ECs derived from normal and malignant colorectal tissues were compared with transcripts from non-endothelial cells, over 170 genes predominantly expressed in the endothelium were identified. Comparison between normal- and tumor-derived endothelium revealed many differentially expressed genes, including a large nujber of genes that were specifically elevated in tumor-associated endothelium. Experiments with representative genes from this group demonstrated that most were similarly expressed in the endothelium of primary lung, breast, brain, and pancreatic cancers as well as in metastatic lesions fo the liver. Theses results demonstrate that neoplastic and normal endothelium in humans are distinct at the molecular level, and have significant implications for the development of anti-angiogenic.

Description:
[0001]     This application claims the benefit of U.S. provisional applications Ser. No. 60/393,023, filed Jul. 2, 2002, and Ser. No. 60/458,964, filed Apr. 1, 2003. 
     
    
       [0002]     The U.S. government retains certain rights in the invention by virtue of the provisions of National Institutes of Heath grants CA57345 and CA43460, which supported this work. 
     
    
     TECHNICAL FIELD OF THE INVENTION  
       [0003]     This invention is related to the area of angiogenesis and anti-angiogenesis. In particular, it relates to genes which are characteristically expressed in tumor endothelial and normal endothelial cells.  
       BACKGROUND OF THE INVENTION  
       [0004]     It is now widely recognized that tumors require a blood supply for expansive growth. This recognition has stimulated a profusion of research on tumor angiogenesis, based on the idea that the vasculature in tumors represents a potential therapeutic target. However, several basic questions about tumor endothelium remain unanswered. For example, are vessels of tumors qualitatively different from normal vessels of the same tissue? What is the relationship of tumor endothelium to endothelium of healing wounds or other physiological or pathological forms of angiogenesis? The answers to these questions critically impact on the potential for new therapeutic approaches to inhibit angiogenesis in a specific manner.  
         [0005]     There is a continuing need in the art to characterize the vasculature of tumors relative to normal vasculature so that any differences can be exploited for therapeutic and diagnostic benefits.  
         [0006]     One technique which can be used to characterize gene expression, or more precisely gene transcription, is termed serial analysis of gene expression (SAGE). Briefly, the SAGE approach is a method for the rapid quantitative and qualitative analysis of mRNA transcripts based upon the isolation and analysis of short defined sequence tags (SAGE Tags) corresponding to expressed genes. Each Tag is a short nucleotide sequences (9-17 base pairs in length) from a defined position in the transcript. In the SAGE method, the Tags are dimerized to reduce bias inherent in cloning or amplification reactions. (See, U.S. Pat. No. 5,695,937) SAGE is particularly suited to the characterization of genes associated with vasculature stimulation or inhibition because it is capable of detecting rare sequences, evaluating large numbers of sequences at one time, and to provide a basis for the identification of previously unknown genes.  
       SUMMARY OF THE INVENTION  
       [0007]     Yet another aspect of the invention is a method for identification of a ligand involved in endothelial cell regulation. A test compound is contacted with a human protein selected from the group consisting of secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midline (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; IK cytokine, down-regulator of HLA II; DnaJ (Hsp40) homolog, subfamily B, member 1; heat shock 70 kD protein 1A; heat shock 70 kD protein 1B; lectin, galactoside-binding, soluble, 1 (galectin 1); heat shock 90 kD protein 1, alpha; DnaJ (Hsp40) homolog, subfamily B, member 1; tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); heat shock 60 kD protein 1 (chaperonin); heat shock 10 kD protein 1 (chaperonin 10); general transcription factor II, i; heat shock 70 kD protein 6 (HSP70B′); heat shock 105 kD; heat shock 105 kD; eukaryotic translation initiation factor 4A, isoform 2; hypothetical protein similar to mouse Fbw5; DKFZP727M231 protein; dynein, cytoplasmic, light polypeptide; hypothetical protein MGC15875; murine retrovirus integration site 1 homolog; hypothetical protein FLJ22376; smoothelin; vacuolar protein sorting 16 (yeast homolog); peanut ( Drosophila )-like 2; hypothetical protein FLJ10350; FK506-binding protein 4 (59 kD); proteasome (prosome, macropain) subunit, beta type, 6; transgelin; sorting nexin 17; ribosomal protein S6 kinase, 90 kD, polypeptide 4; kinesin family member 1C; BTB (POZ) domain containing 2; guanylate cyclase 1, soluble, beta 3; protein-L-isoaspartate (D-aspartate) O-methyltransferase; D-aspartate oxidase; chromosome 9 open reading frame 3; regulator of G-protein signalling 16; voltage-dependent anion channel 3; NS1-binding protein; interferon-induced, hepatitis C-associated microtubular aggregate protein (44 kD); carbonic anhydrase II; protein phosphatase 2, regulatory subunit B (B56), gamma isoform; chromosome 14 open reading frame 3; eukaryotic translation initiation factor 2, subunit 1 (alpha, 35 kD); Rho GTPase activating protein 1; RAP1B, member of RAS oncogene family, profilin 1; DKFZP586L151 protein; hypothetical protein FLJ14987; mitogen-activated protein kinase kinase 1 interacting protein 1; chimerin (chimaerin) 1; hephaestin; KLAA0196 gene product; melanoma-associated antigen recognised by cytotoxic T lymphocytes; HLA class II region expressed gene KE2; histamine N-methyltransferase; hypothetical protein FLJ10842; TIA1 cytotoxic granule-associated RNA-binding protein; N-acylaminoacyl-peptide hydrolase; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12); DKFZP586J0119 protein; hepatocyte growth factor-regulated tyrosine kinase substrate; regulator of G-protein signalling 1; proteasome (prosome, macropain) subunit, beta type, 7; KIAA1402 protein; crystallin, alpha B; protein kinase C, zeta; protein kinase, cAMP-dependent, regulatory, type II, alpha; homologous to yeast nitrogen permease (candidate tumor suppressor); intestinal cell kinase; GS3955 protein; activated p21cdc42Hs kinase; Rho-associated, oiled-coil-containing protein kinase I; KIAA202 protein; unc-51-like kinase 1; and PDGFA associated protein 1. Binding of a test compound to the human protein is determined. A test compound which binds to the protein is identified as a ligand involved in endothelial cell regulation.  
         [0008]     Still another embodiment of the invention provides a method of inhibiting neoangiogenesis in a patient. A molecule comprising an antibody variable region which specifically binds to a TEM protein selected from the group consisting of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; angiopoietin 1; PDGF alpha polypeptide; insulin-like growth factor binding protein; and IK cytokine, down-regulator of HLA II is administered to the patient. Neoangiogenesis in the patient consequently inhibited.  
         [0009]     Yet another aspect of the invention is a method of screening for neoangiogenesis in a patient. A body fluid collected from the patient is contacted with a molecule comprising an antibody variable region which specifically binds to a TEM protein selected from the group consisting of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; angiopoietin 1; PDGF alpha polypeptide; insulin-like growth factor binding protein; and IK cytokine, down-regulator of HLA II. Detection of cross-reactive material in the body fluid with the molecule indicates neoangiogenesis in the patient.  
         [0010]     Also provided by the present invention is a method of promoting neoangiogenesis in a patient. A TEM protein selected from the group consising of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; angiopoietin 1; PDGF alpha polypeptide; insulin-like growth factor binding protein; and IK cytokine, down-regulator of HLA II and, is administered to a patient in need of neoangiogenesis. Neoangiogenesis in the patient is consequently stimulated.  
         [0011]     One embodiment of the invention provides a method of promoting neoangiogenesis in a patient. A nucleic acid molecule encoding a TEM protein selected from the group consising of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VIII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; angiopoietin 1; PDGF alpha polypeptide; insulin-like growth factor binding protein; and IK cytokine, down-regulator of HLA II, is administered to a patient in need of neoangiogenesis. The TEM protein is consequently expressed and neoangiogenesis in the patient is stimulated.  
         [0012]     Another embodiment of the invention provides a method of screening for neoangiogenesis in a patient. A TEM protein selected from the group consisting of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; angiopoietin 1; PDGF alpha polypeptide; insulin-like growth factor binding protein; and IK cytokine, down-regulator of HLA II, is detected in a body fluid collected from the patient. Detection of the TEM protein indicates neoangiogenesis in the patient.  
         [0013]     Another aspect of the invention is a method of screening for neoangiogenesis in a patient. A nucleic acid encoding a TEM protein selected from the group consisting of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; angiopoietin 1; PDGF alpha polypeptide; insulin-like growth factor binding protein; and IK cytokine, down-regulator of HLA D, is detected in a body fluid collected from the patient. Detection of the TEM protein indicates neoangiogenesis in the patient.  
         [0014]     A still further embodiment of the invention is a method to identify candidate drugs for treating tumors. Cells which express one or more TEM genes selected from the group consisting of secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type A, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; IK cytokine, down-regulator of HLA II; DnaJ (Hsp40) homolog, subfamily B, member 1; heat shock 70 kD protein 1A; heat shock 70 kD protein 1B; lectin, galactoside-binding, soluble, 1 (galectin 1); heat shock 90 kD protein 1, alpha; DnaJ (Hsp40) homolog, subfamily B, member 1; tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); heat shock 60 kD protein 1 (chaperonin); heat shock 10 kD protein 1 (chaperonin 10); general transcription factor II, i; heat shock 70 kD protein 6 (HSP70B′); heat shock 105 kD; heat shock 105 kD; eukaryotic translation initiation factor 4A, isoform 2; hypothetical protein similar to mouse Fbw5; DKFZP727M231 protein; dynein, cytoplasmic, light polypeptide; hypothetical protein MGC15875; murine retrovirus integration site 1 homolog; hypothetical protein FLJ22376; smoothelin; vacuolar protein sorting 16 (yeast homolog); peanut ( Drosophila )-like 2; hypothetical protein FLJ10350; FK506-binding protein 4 (59 kD); proteasome (prosome, macropain) subunit, beta type, 6; transgelin; sorting nexin 17; ribosomal protein S6 kinase, 90 kD, polypeptide 4; kinesin family member 1C; BTB (POZ) domain containing 2; guanylate cyclase 1, soluble, beta 3; protein-L-isoaspartate (D-aspartate) O-methyltransferase; D-aspartate oxidase; chromosome 9 open reading frame 3; regulator of G-protein signalling 16; voltage-dependent anion channel 3; NS1-binding protein; interferon-induced, hepatitis C-associated microtubular aggregate protein (44 kD); carbonic anhydrase II; protein phosphatase 2, regulatory subunit B (B56), gamma isoform; chromosome 14 open reading frame 3; eukaryotic translation initiation factor 2, subunit 1 (alpha, 35 kD); Rho GTPase activating protein 1; RAP1B, member of RAS oncogene family, profilin 1; DKFZP586L151 protein; hypothetical protein FLJ14987; mitogen-activated protein kinase kinase 1 interacting protein 1; chimerin (chimaerin) 1; hephaestin; KIAA0196 gene product; melanoma-associated antigen recognised by cytotoxic T lymphocytes; HLA class II region expressed gene KE2; histamine N-methyltransferase; hypothetical protein FLJ10842; TIA1 cytotoxic granule-associated RNA-binding protein; N-acylaminoacyl-peptide hydrolase; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12); DKFZP586J0119 protein; hepatocyte growth factor-regulated tyrosine kinase substrate; regulator of G-protein signalling 1; proteasome (prosome, macropain) subunit, beta type, 7; KIAA1402 protein; crystallin, alpha B; protein kinase C, zeta; protein kinase, cAMP-dependent, regulatory, type II, alpha; homologous to yeast nitrogen permease (candidate tumor suppressor); intestinal cell kinase; GS3955 protein; activated p21cdc42Hs kinase; Rho-associated, oiled-coil-containing protein kinase 1; KIAA2002 protein; unc-51-like kinase 1; and PDGFA associated protein 1, are contacted with a test compound. Expression of said one or more TEM genes is determined by hybridization of mRNA of said cells to a nucleic acid probe which is complementary to said mRNA. A test compound is identified as a candidate drug for treating tumors if it decreases expression of said one or more TEM genes. Optionally the cells are endothelial cells. Alternatively or additionally, the cells are recombinant host cells which are transfected with an expression construct which encodes said one or more TEMs. Test compounds which increase expression can be identified as candidates for promoting wound healing.  
         [0015]     Yet another embodiment of the invention is a method to identify candidate drugs for treating tumors. Cells which express one or more TEM proteins selected from the group consisting of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VL alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; IK cytokine, down-regulator of HLA 1; DnaJ (Hsp40) homolog, subfamily B, member 1; heat shock 70 kD protein 1A; heat shock 70 kD protein 1B; lectin, galactoside-binding, soluble, 1 (galectin 1); heat shock 90 kD protein 1, alpha; DnaJ (Hsp40) homolog, subfamily B, member 1; tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); heat shock 60 kD protein 1 (chaperonin); heat shock 10 kD protein 1 (chaperonin 10); general transcription factor II, i; heat shock 70 kD protein 6 (HSP70B′); heat shock 105 kD; heat shock 105 kD; eukaryotic translation initiation factor 4A, isoform 2; hypothetical protein similar to mouse Fbw5; DKFZP727M231 protein; dynein, cytoplasmic, light polypeptide; hypothetical protein MGC15875; murine retrovirus integration site 1 homolog; hypothetical protein FLJ22376; smoothelin; vacuolar protein sorting 16 (yeast homolog); peanut ( Drosophila )-like 2; hypothetical protein FLJ10350; FK506-binding protein 4 (59 kD); proteasome (prosome, macropain) subunit, beta type, 6; transgelin; sorting nexin 17; ribosomal protein S6 kinase, 90 kD, polypeptide 4; kinesin family member 1C; BTB (POZ) domain containing 2; guanylate cyclase 1, soluble, beta 3; protein-L-isoaspartate (D-aspartate) O-methyltransferase; D-aspartate oxidase; chromosome 9 open reading frame 3; regulator of G-protein signalling 16; voltage-dependent anion channel 3; NS1-binding protein; interferon-induced, hepatitis C-associated microtubular aggregate protein (44 kD); carbonic anhydrase II; protein phosphatase 2, regulatory subunit B (B56), gamma isoform; chromosome 14 open reading frame 3; eukaryotic translation initiation factor 2, subunit 1 (alpha, 35 kD); Rho GTPase activating protein 1; RAP1B, member of RAS oncogene family, profilin 1; DKFZP586L151 protein; hypothetical protein FLJ14987; mitogen-activated protein kinase kinase 1 interacting protein 1; chimerin (chimaerin) 1; hephaestin; KIAA0196 gene product; melanoma-associated antigen recognised by cytotoxic T lymphocytes; HLA class II region expressed gene KE2; histamine N-methyltransferase; hypothetical protein FLJ10842; TIA1 cytotoxic granule-associated RNA-binding protein; N-acylaminoacyl-peptide hydrolase; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12); DKFZP586J0119 protein; hepatocyte growth factor-regulated tyrosine kinase substrate; regulator of G-protein signalling 1; proteasome (prosome, macropain) subunit, beta type, 7; KIAA1402 protein; crystallin, alpha B; protein kinase C, zeta; protein kinase, cAMP-dependent, regulatory, type II, alpha; homologous to yeast nitrogen permease (candidate tumor suppressor); intestinal cell kinase; GS3955 protein; activated p21cdc42Hs kinase; Rho-associated, oiled-coil-containing protein kinase I; KIAA2002 protein; unc-51-like kinase 1; and PDGFA associated protein 1, are contacted with a test compound. The amount of said one or more TEM proteins in said cells is determined. A test compound is identified as a candidate drug for treating tumors if it decreases the amount of one or more TEM proteins in said cells. Optionally the cells are endothelial cells. Alternatively or additionally, the cells are recombinant host cells which are transfected with an expression construct which encodes said one or more TEMs. Alternatively, a test compound which increases the amount of one or more TEM proteins in said cells is identified as a candidate drug for treating wound healing.  
         [0016]     According to another aspect of the invention a method is provided to identify candidate drugs for treating tumors. Cells which express one or more TEM proteins selected from the group consisting of: secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; IK cytokine, down-regulator of LA II; DnaJ (Hsp40) homolog, subfamily B, member 1; heat shock 70 kD protein 1A; heat shock 70 kD protein 1B; lectin, galactoside-binding, soluble, 1 (galectin 1); heat shock 90 kD protein 1, alpha; DnaJ (Hsp40) homolog, subfamily B, member 1; tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); heat shock 60 kD protein 1 (chaperonin); heat shock 10 kD protein 1 (chaperonin 10); general transcription factor II, i; heat shock 70 kD protein 6 (HSP70B′); heat shock 105 kD; heat shock 105 kD; eukaryotic translation initiation factor 4A, isoform 2; hypothetical protein similar to mouse Fbw5; DKFZP727M231 protein; dynein, cytoplasmic, light polypeptide; hypothetical protein MGC15875; murine retrovirus integration site 1 homolog; hypothetical protein FLJ22376; smoothelin; vacuolar protein sorting 16 (yeast homolog); peanut ( Drosophila )-like 2; hypothetical protein FLJ10350; FK506-binding protein 4 (59 kD); proteasome (prosome, macropain) subunit, beta type, 6; transgelin; sorting nexin 17; ribosomal protein S6 kinase, 90 kD, polypeptide 4; kinesin family member 1C; BTB (POZ) domain containing 2; guanylate cyclase 1, soluble, beta 3; protein-L-isoaspartate (D-aspartate) O-methyltransferase; D-aspartate oxidase; chromosome 9 open reading frame 3; regulator of G-protein signalling 16; voltage-dependent anion channel 3; NS I-binding protein; interferon-induced, hepatitis C-associated microtubular aggregate protein (44 kD); carbonic anhydrase II; protein phosphatase 2, regulatory subunit B (B56), gamma isoform; chromosome 14 open reading frame 3; eukaryotic translation initiation factor 2, subunit 1 (alpha, 35 kD); Rho GTPase activating protein 1; RAP 1B, member of RAS oncogene family, profilin 1; DKFZP586L151 protein; hypothetical protein FLJ14987; mitogen-activated protein kinase kinase 1 interacting protein 1; chimerin (chimaerin) 1; hephaestin; KIAA0196 gene product; melanoma-associated antigen recognised by cytotoxic T lymphocytes; HLA class II region expressed gene KE2; histamine N-methyltransferase; hypothetical protein FLJ10842; TIA1 cytotoxic granule-associated RNA-binding protein; N-acylaminoacyl-peptide hydrolase; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12); DKFZP586J0119 protein; hepatocyte growth factor-regulated tyrosine kinase substrate; regulator of G-protein signalling 1; proteasome (prosome, macropain) subunit, beta type, 7; KIAA1402 protein; crystallin, alpha B; protein kinase C, zeta; protein kinase, cAMP-dependent, regulatory, type II, alpha; homologous to yeast nitrogen permease (candidate tumor suppressor); intestinal cell kinase; GS3955 protein; activated p21cdc42Hs kinase; Rho-associated, oiled-coil-containing protein kinase I; KIAA2002 protein; unc-51-like kinase 1; and PDGFA associated protein 1, are contacted with a test compound. Activity of said one or more TEM proteins in said cells is determined. A test compound is identified as a candidate drug for treating tumors if it decreases the activity of one more TEM proteins in said cells. Optionally the cells are endothelial cells. Alternatively or additionally, the cells are recombinant host cells which are transfected with an expression construct which encodes said one or more TEMs. Optionally the cells are endothelial cells. If a test compound increases the acitivity of one more TEM proteins in said cells it can be identified as a candidate drug for treating wound healing.  
         [0017]     An additional aspect of the invention is a method to identify candidate drugs for treating patients bearing tumors. A test compound is contacted with recombinant host cells which are transfected with an expession construct which encodes one or more TEM proteins selected from the group consisting of secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; IK cytokine, down-regulator of HLA II; DnaJ (Hsp40) homolog, subfamily B, member 1; heat shock 70 kD protein 1A; heat shock 70 kD protein 1B; lectin, galactoside-binding, soluble, 1 (galectin 1); heat shock 90 kD protein 1, alpha; DnaJ (Hsp40) homolog, subfamily B, member 1; tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); heat shock 60 kD protein 1 (chaperonin); heat shock 10 kD protein 1 (chaperonin 10); general transcription factor II, i; heat shock 70 kD protein 6 (HSP70B′); heat shock 105 kD; heat shock 105 kD; eukaryotic translation initiation factor 4A, isoform 2; hypothetical protein similar to mouse Fbw5; DKFZP727M231 protein; dynein, cytoplasmic, light polypeptide; hypothetical protein MGC15875; murine retrovirus integration site 1 homolog; hypothetical protein FLJ22376; smoothelin; vacuolar protein sorting 16 (yeast homolog); peanut ( Drosophila )-like 2; hypothetical protein FLJ10350; FK506-binding protein 4 (59 kD); proteasome (prosome, macropain) subunit, beta type, 6; transgelin; sorting nexin 17; ribosomal protein S6 kinase, 90 kD, polypeptide 4; kinesin family member 1C; BTB (POZ) domain containing 2; guanylate cyclase 1, soluble, beta 3; protein-L-isoaspartate (D-aspartate) O-methyltransferase; D-aspartate oxidase; chromosome 9 open reading frame 3; regulator of G-protein signalling 16; voltage-dependent anion channel 3; NS1-binding protein; interferon-induced, hepatitis C-associated microtubular aggregate protein (44 kD); carbonic anhydrase II; protein phosphatase 2, regulatory subunit B (B56), gamma isoform; chromosome 14 open reading frame 3; eukaryotic translation initiation factor 2, subunit 1 (alpha, 35 kD); Rho GTPase activating protein 1; RAP1B, member of RAS oncogene family; profilin 1; DKFZP586L151 protein; hypothetical protein FLJ14987; mitogen-activated protein kinase kinase 1 interacting protein 1; chimerin (chimaerin) 1; hephaestin; KIAA0196 gene product; melanoma-associated antigen recognised by cytotoxic T lymphocytes; HLA class II region expressed gene KE2; histamine N-methyltransferase; hypothetical protein FLJ10842; TIA1 cytotoxic granule-associated RNA-binding protein; N-acylaminoacyl-peptide hydrolase; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12); DKFZP586J0119 protein; hepatocyte growth factor-regulated tyrosine kinase substrate; regulator of G-protein signalling 1; proteasome (prosome, macropain) subunit, beta type, 7; KIAA1402 protein; crystallin, alpha B; protein kinase C, zeta; protein kinase, cAMP-dependent, regulatory, type II, alpha; homologous to yeast nitrogen permease (candidate tumor suppressor); intestinal cell kinase; GS3955 protein; activated p21cdc42Hs kinase; Rho-associated, oiled-coil-containing protein kinase I; KIAA2002 protein; unc-51-like kinase 1; and PDGFA associated protein 1. Proliferation of said cells is determined. A test compound which inhibits proliferation of said cells is identified as a candidate drug for treating patients bearing tumors. A test coumpound which stimulates proliferation of said cells is identified as a candidate drug for promoting neoangiogenesis, such as for use in wound healing.  
         [0018]     Another aspect of the invention is a method for identifying endothelial cells. One or more antibodies which bind specifically to a TEM protein selected from the group consisting of secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; IK cytokine, down-regulator of HLA II; DnaJ (Hsp40) homolog, subfamily B, member 1; heat shock 70 kD protein 1A; heat shock 70 kD protein 1B; lectin, galactoside-binding, soluble, 1 (galectin 1); heat shock 90 kD protein 1, alpha; DnaJ (Hsp40) homolog, subfamily B, member 1; tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); heat shock 60 kD protein 1 (chaperonin); heat shock 105 kD protein 1 (chaperonin 10); general transcription factor II, i; heat shock 70 kD protein 6 (HSP70B′); heat shock 105 kD; heat shock 105 kD; eukaryotic translation initiation factor 4A, isoform 2; hypothetical protein similar to mouse Fbw5; DKFZP727M231 protein; dynein, cytoplasmic, light polypeptide; hypothetical protein MGC15875; murine retrovirus integration site 1 homolog; hypothetical protein FLJ22376; smoothelin; vacuolar protein sorting 16 (yeast homolog); peanut ( Drosophila )-like 2; hypothetical protein FLJ10350; FK506-binding protein 4 (59 kD); proteasome (prosome, macropain) subunit, beta type, 6; transgelin; sorting nexin 17; ribosomal protein S6 kinase, 90 kD, polypeptide 4; kinesin family member 1C; BTB (POZ) domain containing 2; guanylate cyclase 1, soluble, beta 3; protein-L-isoaspartate (D-aspartate) O-methyltransferase; D-aspartate oxidase; chromosome 9 open reading frame 3; regulator of G-protein signalling 16; voltage-dependent anion channel 3; NS1-binding protein; interferon-induced, hepatitis C-associated microtubular aggregate protein (44 kD); carbonic anhydrase II; protein phosphatase 2, regulatory subunit B (B56), gamma isoform; chromosome 14 open reading frame 3; eukaryotic translation initiation factor 2, subunit 1 (alpha, 35 kD); Rho GTPase activating protein 1; RAP1B, member of RAS oncogene family, profilin 1; DKFZP586L151 protein; hypothetical protein FLJ14987; mitogen-activated protein kinase kinase 1 interacting protein 1; chimerin (chimaerin) 1; hephaestin; KIAA0196 gene product; melanoma-associated antigen recognised by cytotoxic T lymphocytes; HLA class II region expressed gene KE2; histamine N-methyltransferase; hypothetical protein FLJ10842; TIA1 cytotoxic granule-associated RNA-binding protein; N-acylaminoacyl-peptide hydrolase; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12); DKFZP586J0119 protein; hepatocyte growth factor-regulated tyrosine kinase substrate; regulator of G-protein signalling 1; proteasome (prosome, macropain) subunit, beta type, 7; KIAA1402 protein; crystallin, alpha B; protein kinase C, zeta; protein kinase, cAMP-dependent, regulatory, type II, alpha; homologous to yeast nitrogen permease (candidate tumor suppressor); intestinal cell kinase; GS3955 protein; activated p21cdc42Hs kinase; Rho-associated, oiled-coil-containing protein kinase I; KIAA2002 protein; unc-51-like kinase 1; and PDGFA associated protein 1, is contacted with a population of cells. Cells in the population which have bound to said antibodies are detected. Cells which are bound to said antibodies are identified as endothelial cells. Optionally cells which have bound to said antibodies are isolated from cells which have not bound.  
         [0019]     Still another aspect of the invention is a method for identifying endothelial cells. One or more nucleic acid hybridization probes which are complementary to a TEM gene nucleic acid sequence selected from the group consisting of secreted protein, acidic, cysteine-rich (osteonectin); collagen, type I, alpha 1; collagen, type IV, alpha 1; collagen, type XVIII, alpha 1; fibronectin 1; collagen, type IV, alpha 2;  Homo sapiens  mRNA; cDNA DKFZp586J021 (from clone DKFZp586J021); collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); collagen, type VI, alpha 2; collagen, type XVIII, alpha 1; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); transforming growth factor, beta-induced, 68 Kd; Biglycan; collagen, type VI, alpha 1; small inducible cytokine subfamily B (Cys-X-Cys), member 14 (BRAK); spondin 2, extracellular matrix protein; Fibromodulin; laminin, alpha 4; collagen, type IV, alpha 1; complement component 1, s subcomponent; fibulin 1; frizzled-related protein; lysyl oxidase-like 2; plasminogen activator, urokinase; natural killer cell transcript 4; microfibrillar-associated protein 2; collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive); follistatin-like 1; complement component 1, r subcomponent; Decorin; secreted protein, acidic, cysteine-rich (osteonectin); Thy-1 cell surface antigen; cysteine-rich, angiogenic inducer, 61; immunoglobulin lambda locus; hypothetical protein CAB56184; serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1; collagen, type I, alpha 1; collagen, type V, alpha 2; laminin, beta 1; DKFZP586B0621 protein; cysteine knot superfamily 1, BMP antagonist 1; hypothetical protein FLJ23053; hypothetical protein FLJ20397; matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase); insulin-like growth factor binding protein 7; collagen, type V, alpha 1; thrombospondin 2; midkine (neurite growth-promoting factor 2); DKFZP564I1922 protein; fibrillin 1 (Marfan syndrome); transforming growth factor, beta 1; serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1; galactosidase, beta 1; IK cytokine, down-regulator of HLA II; DnaJ (Hsp40) homolog, subfamily B, member 1; heat shock 70 kD protein 1A; heat shock 70 kD protein 1B; lectin, galactoside-binding, soluble, 1 (galectin 1); heat shock 90 kD protein 1, alpha; DnaJ (Hsp40) homolog, subfamily B, member 1; tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); heat shock 60 kD protein 1 (chaperonin); heat shock 10 kD protein 1 (chaperonin 10); general transcription factor II, i; heat shock 70 kD protein 6 (HSP70B′); heat shock 105 kD; heat shock 105 kD; eukaryotic translation initiation factor 4A, isoform 2; hypothetical protein similar to mouse Fbw5; DKFZP727M231 protein; dynein, cytoplasmic, light polypeptide; hypothetical protein MGC15875; murine retrovirus integration site 1 homolog; hypothetical protein FLJ22376; smoothelin; vacuolar protein sorting 16 (yeast homolog); peanut ( Drosophila )-like 2; hypothetical protein FLJ10350; FK506-binding protein 4 (59 kD); proteasome (prosome, macropain) subunit, beta type, 6; transgelin; sorting nexin 17; ribosomal protein S6 kinase, 90 kD, polypeptide 4; kinesin family member 1C; BTB (POZ) domain containing 2; guanylate cyclase 1, soluble, beta 3; protein-L-isoaspartate (D-aspartate) O-methyltransferase; D-aspartate oxidase; chromosome 9 open reading frame 3; regulator of G-protein signalling 16; voltage-dependent anion channel 3; NS1-binding protein; interferon-induced, hepatitis C-associated microtubular aggregate protein (44 kD); carbonic anhydrase II; protein phosphatase 2, regulatory subunit B (B56), gamma isoform; chromosome 14 open reading frame 3; eukaryotic translation initiation factor 2, subunit 1 (alpha, 35 kD); Rho GTPase activating protein 1; RAP1B, member of RAS oncogene family; profilin 1; DKFZP586L151 protein; hypothetical protein FLJ14987; mitogen-activated protein kinase kinase 1 interacting protein 1; chimerin (chimaerin) 1; hephaestin; KIAA0196 gene product; melanoma-associated antigen recognised by cytotoxic T lymphocytes; HLA class II region expressed gene KE2; histamine N-methyltransferase; hypothetical protein FLJ10842; TIA1 cytotoxic granule-associated RNA-binding protein; N-acylaminoacyl-peptide hydrolase; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12); DKFZP586J0119 protein; hepatocyte growth factor-regulated tyrosine kinase substrate; regulator of G-protein signalling 1; proteasome (prosome, macropain) subunit, beta type, 7; KIAA1402 protein; crystallin, alpha B; protein kinase C, zeta; protein kinase, cAMP-dependent, regulatory, type II, alpha; homologous to yeast nitrogen permease (candidate tumor suppressor); intestinal cell kinase; GS3955 protein; activated p21cdc42Hs kinase; Rho-associated, oiled-coil-containing protein kinase I; KLAA2002 protein; unc-51-like kinase 1; and PDGFA associated protein 1, is contacted with nucleic acids of a population of cells. Nucleic acids which have specifically hybridized to said nucleic acid hybridization probes are detected. Cells whose nucleic acids specifically hybridized are identified as endothelial cells.  
         [0020]     These and other embodiments which will be apparent to those of skill in the art upon reading the specification provide the art with reagents and methods for detection, diagnosis, therapy, and drug screening pertaining to neoangiogenesis and pathological processes involving or requiring neoangiogenesis.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0021]     We identified 123 human genes that were expressed at significantly higher levels (&gt;2-fold) in tumor endothelium than in normal endothelium. See Tables 1 and 3, which show extracellular and cytoplasmic tumor endothelial markers (TEMs) respectively. Tables 2 and 4 identify the structure of the genes, proteins, and mRNAs that correspond to the tags identified. See also Tables 5, 6, and 7. Most of these genes were either not expressed or expressed at relatively low levels in Endothelial Cells (ECs) maintained in culture. Interestingly, the tumor endothelium genes were expressed in all tumors tested, regardless of its tissue or organ source. Most tumor endothelium genes were also expressed in corpus luteum and wounds.  
                                                   TABLE 1                           Extracellular tumor endothelial markers.            SEQ                   ID NO   StdTag   Function                    1   ATGTGAAGAG   secreted protein, acidic,                   cysteine-rich (osteonectin)               2   ACCAAAAACC   collagen, type I, alpha 1               3   GACCGCAGGA   collagen, type IV, alpha 1               4   TAATCCTCAA   collagen, type XVIII, alpha 1               5   ATCTTGTTAC   fibronectin 1               6   TTCTCCCAAA   collagen, type IV, alpha 2               7   TCTCTGATGC   Homo sapiens mRNA; cDNA               DKFZp586J021 (from clone               DKFZp586J021)               8   GATCAGGCCA   collagen, type III, alpha 1               (Ehlers-Danlos syndrome type IV,               autosomal dominant)               9   GTGCTAAGCG   collagen, type VI, alpha 2               10   GACAGGCTGG   collagen, type XVIII, alpha 1               11   CGTCTTTAAA   collagen, type III, alpha 1               (Ehlers-Danlos syndrome type IV,               autosomal dominant)               12   GTGTGTTTGT   transforming growth factor,               beta-induced, 68 Kd               13   GCCTGTCCCT   Biglycan               14   TTGCTGACTT   collagen, type VI, alpha 1               15   CAGGTTTCAT   small inducible cytokine               subfamily B (Cys-X-Cys), member               14 (BRAK)               16   TTATGGATCT   spondin 2, extracellular matrix               protein               17   AGTGGTGGCT   Fibromodulin               18   ACAGAGCACA   laminin, alpha 4               19   GTGCTACTTC   collagen, type IV, alpha 1               20   ACTGAAAGAA   complement component 1,               s subcomponent               21   CAGCTGGCCA   fibulin 1               22   CTGTTACCAG   frizzled-related protein               23   TGTCATCACA   lysyl oxidase-like 2               24   ACCTGTGACC   plasminogen activator, urokinase               25   TCCTCTTTCC   natural killer cell transcript 4               26   GACCACCTTT   microfibrillar-associated               protein 2               27   GTGCTGATTC   collagen, type VII, alpha 1               (epidermolysis bullosa, dystrophic,               dominant and recessive)               28   CCGTGACTCT   follistatin-like 1               29   TTCTGTGCTG   complement component 1,               r subcomponent               30   ACTTATTATG   Decorin               31   TTAGTGTCGT   secreted protein, acidic,               cysteine-rich (osteonectin)               32   GCTGGTGCCT   Thy-1 cell surface antigen               33   AGTGTCTGTG   cysteine-rich, angiogenic               inducer, 61               34   AAGGGAGCAC   immunoglobulin lambda locus               35   AATTCTGTAA   hypothetical protein CAB56184               36   GTCTGTCAGG   serine (or cysteine) proteinase               inhibitor, clade G (C1               inhibitor), member 1               37   CCGGGGGAGC   collagen, type 1, alpha 1               38   GACGATCAAG   collagen, type V, alpha 2               39   CTTGTAACAG   laminin, beta 1               40   GGGCAGTGGC   DKFZP586B0621 protein               41   AATCTGTAAC   cysteine knot superfamily 1,               BMP antagonist 1               42   GCTATCACAT   hypothetical protein FLJ23053               43   TTTGAAAATT   hypothetical protein FLJ20397               44   TAAATCCCCA   matrix metalloproteinase 9               (gelatinase B, 92 kD gelatinase,               92 kD type IV collagenase)               45   GATAACTACA   insulin-like growth factor               binding protein 7               46   TGATTCTGTT   collagen, type V, alpha 1               47   GTCAAAATTT   thrombospondin 2               48   CCCTGCCTTG   midkine (neurite growth-               promoting factor 2)               49   ACTGCTTTAC   DKFZP564I1922 protein               50   TGCAATATGC   fibrillin 1 (Marfan syndrome)               51   ATCGTGCGCT   transforming growth factor,               beta 1               52   ACATAGACCG   serine (or cysteine) proteinase               inhibitor, clade F (alpha-2               antiplasmin, pigment epithelium               53   TTACCTTTTT   galactosidase, beta 1               54   GCTGTGGATA   IK cytokine, down-regulator of               HLA II                  
 
         [0022]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                   
               
               
                 Extracellular tumor endothelial markers: identification of tags 
               
               
                 with gene sequences. 
               
             
          
           
               
                 SEQ ID NO 
                 Unigene ID 
                 gene symbol 
                 locuslink id 
                 OMIMID 
                 mRNA 
                 Signal Seq 
               
               
                   
               
               
                  1 
                 Hs.111779 
                 SPARC 
                 6678 
                 182120 
                 NM_003118 
                 yes 
               
               
                  2 
                 Hs.172928 
                 COL1A1 
                 1277 
                 120150 
                 NM_000088 
                 yes 
               
               
                  3 
                 Hs.119129 
                 COL4A1 
                 1282 
                 120130 
                 NM_001845 
                 yes 
               
               
                  4 
                 Hs.78409 
                 COL18A1 
                 80781  
                 120328 
                 AF018081 
                 yes 
               
               
                  5 
                 Hs.287820 
                 FN1 
                 2335 
                 135600 
                 NM_002026 
                 yes 
               
               
                  6 
                 Hs.75617 
                 COL4A2 
                 1284 
                 120090 
                 NM_001846 
               
               
                  7 
                 Hs.6441 
                   
                   
                   
                 NM_003255 
                 yes 
               
               
                  8 
                 Hs.119571 
                 COL3A1 
                 1281 
                 120180 
                 NM_000090 
                 yes 
               
               
                  9 
                 Hs.159263 
                 COL6A2 
                 1292 
                 120240 
                 NM_001849 
                 yes 
               
               
                 10 
                 Hs.78409 
                 COL18A1 
                 80781  
                 120328 
                 AF018081 
                 yes 
               
               
                 11 
                 Hs.119571 
                 COL3A1 
                 1281 
                 120180 
                 NM_000090 
                 yes 
               
               
                 12 
                 Hs.118787 
                 TGFBI 
                 7045 
                 601692 
                 NM_000358 
                 yes 
               
               
                 13 
                 Hs.821 
                 BGN 
                  633 
                 301870 
                 BC004244 
                 yes 
               
               
                 14 
                 Hs.108885 
                 COL6A1 
                 1291 
                 120220 
                 NM_001848 
                 yes 
               
               
                 15 
                 Hs.24395 
                 SCYB14 
                 9547 
                 604186 
                 AF144103 
                 yes 
               
               
                 16 
                 Hs.288126 
                 SPON2 
                 10417  
                 605918 
                 NM_012445 
                 no 
               
               
                 17 
                 Hs.230 
                 FMOD 
                 2331 
                 600245 
                 NM_002023 
                 yes 
               
               
                 18 
                 Hs.78672 
                 LAMA4 
                 3910 
                 600133 
                 NM_002290 
                 yes 
               
               
                 19 
                 Hs.119129 
                 COL4A1 
                 1282 
                 120130 
                 NM_001845 
                 yes 
               
               
                 20 
                 Hs.169756 
                 C1S 
                  716 
                 120580 
                 NM_001734 
                 yes 
               
               
                 21 
                 Hs.79732 
                 FBLN1 
                 2192 
                 135820 
                 NM_006485 
                 yes 
               
               
                 22 
                 Hs.153684 
                 FRZB 
                 2487 
                 605083 
                 NM_001463 
                 yes 
               
               
                 23 
                 Hs.83354 
                 LOXL2 
                 4017 
                   
                 NM_002318 
                 yes 
               
               
                 24 
                 Hs.77274 
                 PLAU 
                 5328 
                 191840 
                 NM_002658 
                 yes 
               
               
                 25 
                 Hs.943 
                 NK4 
                 9235 
                 606001 
                 NM_004221 
                 no 
               
               
                 26 
                 Hs.83551 
                 MFAP2 
                 4237 
                 156790 
                 NM_002403, NM —   
                 yes 
               
               
                 27 
                 Hs.1640 
                 COL7A1 
                 1294 
                 120120 
                 NM_000094 
                 yes 
               
               
                 28 
                 Hs.296267 
                 FSTL1 
                 11167  
                 605547 
                 NM_007085 
                 yes 
               
               
                 29 
                 Hs.1279 
                 C1R 
                  715 
                 216950 
                 NM_001733 
                 yes 
               
               
                 30 
                 Hs.76152 
                 DCN 
                 1634 
                 125255 
                 NM_001920 
                 yes 
               
               
                 31 
                 Hs.111779 
                 SPARC 
                 6678 
                 182120 
                 NM_003118 
                 yes 
               
               
                 32 
                 Hs.125359 
                 THY1 
                 7070 
                 188230 
                 NM_006288 
                 yes 
               
               
                 33 
                 Hs.8867 
                 CYR61 
                 3491 
                 602369 
                 NM_001554 
                 yes 
               
               
                 34 
                 Hs.181125 
                 IGLC3 
                 3538 
                   
                 D01059 
                 yes 
               
               
                 35 
                 Hs.241575 
                   
                   
                   
                 NM_032520 
                 Yes 
               
               
                 36 
                 Hs.151242 
                 SERPING1 
                  710 
                 106100 
                 NM_000062 
                 yes 
               
               
                 37 
                 Hs.172928 
                 COL1A1 
                 1277 
                 120150 
                 NM_000088 
                 yes 
               
               
                 38 
                 Hs.82985 
                 COL5A2 
                 1290 
                 120190 
                 NM_000393 
                 no 
               
               
                 39 
                 Hs.82124 
                 LAMB1 
                 3912 
                 150240 
                 NM_002291 
                 yes 
               
               
                 40 
                 Hs.157211 
                   
                   
                   
                 NM_015645 
                 yes 
               
               
                 41 
                 Hs.40098 
                 CKTSF1B1 
                 26585  
                 603054 
                 NM_013372 
                 yes 
               
               
                 42 
                 Hs.94037 
                   
                   
                   
                 NM_022907 
                 yes 
               
               
                 43 
                 Hs.272688 
                   
                   
                   
                 NM_017802 
                 no 
               
               
                 44 
                 Hs.151738 
                 MMP9 
                 4318 
                 120361 
                 NM_004994 
                 yes 
               
               
                 45 
                 Hs.119206 
                 IGFBP7 
                 3490 
                 602867 
                 NM_001553 
                 yes 
               
               
                 46 
                 Hs.146428 
                 COL5A1 
                 1289 
                 120215 
                 NM_000093 
                 yes 
               
               
                 47 
                 Hs.108623 
                 THBS2 
                 7058 
                 188061 
                 NM_003247 
                 yes 
               
               
                 48 
                 Hs.82045 
                 MDK 
                 4192 
                 162096 
                 NM_002391 
                 yes 
               
               
                 49 
                 Hs.72157 
                   
                   
                   
                 AF245505 
                 yes 
               
               
                 50 
                 Hs.750 
                 FBN1 
                 2200 
                 134797 
                 NM_000138 
                 no 
               
               
                 51 
                 Hs.1103 
                 TGFB1 
                 7040 
                 190180 
                 NM_000660 
                 yes 
               
               
                 52 
                 Hs.173594 
                 SERPINF1 
                 5176 
                 172860 
                 NM_002615 
                 yes 
               
               
                 53 
                 Hs.79222 
                 GLB1 
                 2720 
                 230500 
                 NM_000404 
                 yes 
               
               
                 54 
                 Hs.8024 
                 IK 
                 3550 
                 600549 
                 NM_006083 
                 no 
               
               
                   
               
             
          
         
       
     
         [0023]    
       
         
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                   
               
               
                 Cytoplasmic tumor endothelial markers. 
               
             
          
           
               
                 SEQ ID 
                 StdTag 
                 Function 
               
               
                   
               
             
          
           
               
                 55 
                 AGACCA 
                 DnaJ (Hsp40) homolog, subfamily B, 
                   
               
               
                   
                   
                 member 1 
               
               
                   
               
               
                 56 
                 CAGAG 
                 heat shock 70 kD protein 1A 
               
               
                   
               
               
                 57 
                 AAGAG 
                 heat shock 70 kD protein 1B 
               
               
                   
               
               
                 58 
                 GCCCC 
                 lectin, galactoside-binding, soluble, 
               
               
                   
                   
                 1 (galectin 1) 
               
               
                   
               
               
                 59 
                 TACTAG 
                 heat shock 90 kD protein 1, alpha 
               
               
                   
               
               
                 60 
                 AGAGG 
                 DnaJ (Hsp40) homolog, subfamily B, 
               
               
                   
                   
                 member 1 
               
               
                   
               
               
                 61 
                 GAGAG 
                 tissue inhibitor of metalioproteinase 
               
               
                   
                   
                 1 (erythroid potentiating activity, 
               
               
                   
                   
                 collagenase inhibitor) 
               
               
                   
               
               
                 62 
                 TACCAG 
                 heat shock 60 kD protein 1 
               
               
                   
                   
                 (chaperonin) 
               
               
                   
               
               
                 63 
                 TAAATA 
                 heat shock 10 kD protein 1 
               
               
                   
                   
                 (chaperonin 10) 
               
               
                   
               
               
                 64 
                 CCTTTC 
                 general transcription factor II, I 
               
               
                   
               
               
                 65 
                 TGAAAG 
                 heat shock 70 kD protein 6 (HSP70B′) 
               
               
                   
               
               
                 66 
                 TGAAAG 
                 heat shock 105 kD 
               
               
                   
               
               
                 67 
                 TGAACC 
                 heat shock 105 kD 
               
               
                   
               
               
                 68 
                 TCTTAA 
                 eukaryotic translation initiation 
               
               
                   
                   
                 factor 4A, isoform 2 
               
               
                   
               
               
                 69 
                 TCCACG 
                 hypothetical protein similar to mouse 
               
               
                   
                   
                 Fbw5 
               
               
                   
               
               
                 70 
                 GGGCC 
                 DKFZP727M231 protein 
               
               
                   
               
               
                 71 
                 GACTGT 
                 dynein, cytoplasmic, light 
               
               
                   
                   
                 polypeptide 
               
               
                   
               
               
                 72 
                 CACACC 
                 hypothetical protein MGC15875 
               
               
                   
               
               
                 73 
                 TTGTTA 
                 murine retrovirus integration site 1 
               
               
                   
                   
                 homolog 
               
               
                   
               
               
                 74 
                 GAAGAA 
                 hypothetical protein FLJ22376 
               
               
                   
               
               
                 75 
                 GCCAG 
                 Smoothelin 
               
               
                   
               
               
                 76 
                 GTAGCA 
                 vacuolar protein sorting 16 (yeast 
               
               
                   
                   
                 homolog) 
               
               
                   
               
               
                 77 
                 CCGGC 
                 peanut (Drosophila)-like 2 
               
               
                   
               
               
                 78 
                 CCCCCT 
                 hypothetical protein FLJ10350 
               
               
                   
               
               
                 79 
                 CTTGAG 
                 FK506-binding protein 4 (59 kD) 
               
               
                   
               
               
                 80 
                 GAGCG 
                 proteasome (prosome, macropain) 
               
               
                   
                   
                 subunit, beta type, 6 
               
               
                   
               
               
                 81 
                 ACAGG 
                 transgelin 
               
               
                   
               
               
                 82 
                 GGCCA 
                 sorting nexin 17 
               
               
                   
               
               
                 83 
                 GTCACT 
                 ribosomal protein S6 kinase, 90 kD, 
               
               
                   
                   
                 polypeptide 4 
               
               
                   
               
               
                 84 
                 AGGAT 
                 kinesin family member 1C 
               
               
                   
               
               
                 85 
                 CCCCC 
                 BTB (POZ) domain containing 2 
               
               
                   
               
               
                 86 
                 TTAATG 
                 guanylate cyclase 1, soluble, beta 3 
               
               
                   
               
               
                 87 
                 CTGTGT 
                 protein-L-isoaspartate (D-aspartate) 
               
               
                   
                   
                 O-methyitransferase 
               
               
                   
               
               
                 88 
                 CCTATA 
                 D-aspartate oxidase 
               
               
                   
               
               
                 89 
                 GCTGG 
                 chromosome 9 open reading frame 3 
               
               
                   
               
               
                 90 
                 CTTTGA 
                 regulator of G-protein signalling 16 
               
               
                   
               
               
                 91 
                 ACTGGT 
                 voltage-dependent anion channel 3 
               
               
                   
               
               
                 92 
                 CTGTAC 
                 NS1-binding protein 
               
               
                   
               
               
                 93 
                 ATTTAG 
                 interferon-induced, hepatitis 
               
               
                   
                   
                 C-associated microtubular aggregate 
               
               
                   
                   
                 protein (44 kD) 
               
               
                   
               
               
                 94 
                 ATTTCA 
                 carbonic anhydrase II 
               
               
                   
               
               
                 95 
                 GGGGG 
                 protein phosphatase 2, regulatory 
               
               
                   
                   
                 subunit B (B56), gamma isoform 
               
               
                   
               
               
                 96 
                 TTTTCT 
                 chromosome 14 open reading frame 3 
               
               
                   
               
               
                 97 
                 CCTGTA 
                 eukaryotic translation initiation 
               
               
                   
                   
                 factor 2, subunit 1 (alpha, 35 kD 
               
               
                   
               
               
                 98 
                 TATTTC 
                 Rho GTPase activating protein 1 
               
               
                   
               
               
                 99 
                 CAAGG 
                 RAP1B, member of RAS oncogene family 
               
               
                   
               
               
                 100 
                 GGCTG 
                 profilin 1 
               
               
                   
               
               
                 101 
                 TCATCT 
                 DKFZP586L 151 protein 
               
               
                   
               
               
                 102 
                 TCGTAA 
                 hypothetical protein FLJ14987 
               
               
                   
               
               
                 103 
                 ATAGTA 
                 mitogen-activated protein kinase 
               
               
                   
                   
                 kinase 1 interacting protein 1 
               
               
                   
               
               
                 104 
                 CCTACA 
                 chimerin (chimaerin) 1 
               
               
                   
               
               
                 105 
                 TTTTAG 
                 hephaestin 
               
               
                   
               
               
                 106 
                 CAATTT 
                 KIAA0196 gene product 
               
               
                   
               
               
                 107 
                 CACCTT 
                 melanoma-associated antigen by 
               
               
                   
                   
                 cytotoxic T lymphocytes 
               
               
                   
               
               
                 108 
                 GTGGG 
                 HLA class II region expressed gene 
               
               
                   
                   
                 kE2 
               
               
                   
               
               
                 109 
                 GATATA 
                 histamine N-methyltransferase 
               
               
                   
               
               
                 110 
                 TCTTAA 
                 hypothetical protein FLJ10842 
               
               
                   
               
               
                 111 
                 TGAAAA 
                 TIA1 cytotoxic granule-associated 
               
               
                   
                   
                 RNA-binding protein 
               
               
                   
               
               
                 112 
                 AGCTGA 
                 N-acylaminoacyl-peptide hydrolase 
               
               
                   
               
               
                 113 
                 GTCCCA 
                 integrin, beta 1 (fibronectin 
               
               
                   
                   
                 receptor, beta polypeptide, antigen 
               
               
                   
                   
                 CD29 includes MDF2, 
               
               
                   
               
               
                 114 
                 TTGCG 
                 DKFZP586J0119 protein 
               
               
                   
               
               
                 115 
                 GTCTGT 
                 hepatocyte growth factor-regulated 
               
               
                   
                   
                 tyrosine kinase substrate 
               
               
                   
               
               
                 116 
                 TCCTTG 
                 regulator of G-protein signalling 1 
               
               
                   
               
               
                 117 
                 TGGCTA 
                 proteasome (prosome, macropain) 
               
               
                   
                   
                 subunit, beta type, 7 
               
               
                   
               
               
                 118 
                 TCTTCT 
                 KIAA1402 protein 
               
               
                   
               
               
                 119 
                 GTTTCA 
                 crystallin, alpha B 
               
               
                   
               
               
                 120 
                 CGCATT 
                 protein kinase C, zeta 
               
               
                   
               
               
                 121 
                 ATCGTG 
                 protein kinase, cAMP-dependent, 
               
               
                   
                   
                 regulatory, type II, alpha 
               
               
                   
               
               
                 122 
                 AGCTG 
                 homologous to yeast nitrogen permease 
               
               
                   
                   
                 (candidate tumor suppressor) 
               
               
                   
               
               
                 123 
                 CTCCAC 
                 PDGFA associated protein 
               
               
                   
               
             
          
         
       
     
         [0024]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                   
               
               
                 Cytoplasmic tumor endothelial markers: identification of tags 
               
               
                 with gene sequences. 
               
             
          
           
               
                 SEQ ID NO 
                 Unigene ID 
                 33gene symbol 
                 locuslink id 
                 OMIMID 
                 mRNA 
                 Signal Seq 
               
               
                   
               
               
                 55 
                 Hs.82646 
                 DNAJB1 
                 3337 
                 604572 
                 NM_006145 
                 No 
               
               
                 56 
                 Hs.8997 
                 HSPA1A 
                 3303 
                 140550 
                 NM_005345 
                 No 
               
               
                 57 
                 Hs.274402 
                 HSPA1B 
                 3304 
                 603012 
                 NM_005346 
                 No 
               
               
                 58 
                 Hs.227751 
                 LGALS1 
                 3956 
                 150570 
                 NM_002305 
                 No 
               
               
                 59 
                 Hs.289088 
                 HSPCA 
                 3320 
                 140571 
                 NM_005348 
                 No 
               
               
                 60 
                 Hs.82646 
                 DNAJB1 
                 3337 
                 604572 
                 NM_006145 
                 No 
               
               
                 61 
                 Hs.5831 
                 TIMP1 
                 7076 
                 305370 
                 NM_003254 
                 No 
               
               
                 62 
                 Hs.79037 
                 HSPD1 
                 3329 
                 118190 
                 BC010112 
                 No 
               
               
                 63 
                 Hs.1197 
                 HSPE1 
                 3336 
                 600141 
                 NM_002157 
                 No 
               
               
                 64 
                 Hs.278589 
                 GTF2I 
                 2969 
                 601679 
                 NM_032999 
                 No 
               
               
                 65 
                 Hs.3268 
                 HSPA6 
                 3310 
                 140555 
                 NM_002155 
                 No 
               
               
                 66 
                 Hs.36927 
                 HSP105B 
                 10808  
                   
                 NM_006644 
                 No 
               
               
                 67 
                 Hs.36927 
                 HSP105B 
                 10808  
                   
                 NM_006644 
                 No 
               
               
                 68 
                 Hs.173912 
                 EIF4A2 
                 1974 
                 601102 
                 NM_001967 
                 No 
               
               
                 69 
                 Hs.82023 
                   
                   
                   
                 BC014130 
                 No 
               
               
                 70 
                 Hs.168073 
                   
                   
                   
                   
                 No 
               
               
                 71 
                 Hs.5120 
                 PIN 
                 8655 
                 601562 
                 NM_003746 
                 No 
               
               
                 72 
                 Hs.315054 
                   
                   
                   
                 NM_032921 
                 No 
               
               
                 73 
                 Hs.251385 
                 MRVI1 
                 10335  
                 604673 
                 NM_006069 
                 No 
               
               
                 74 
                 Hs.29341 
                   
                   
                   
                 NM_022760 
                 No 
               
               
                 75 
                 Hs.149098 
                 SMTN 
                 6525 
                 602127 
                 AF064238 
                 No 
               
               
                 76 
                 Hs.302441 
                   
                   
                   
                 NM_022575 
                 No 
               
               
                 77 
                 Hs.155524 
                 PNUTL2 
                 5414 
                 603696 
                 NM_004574 
                 No 
               
               
                 78 
                 Hs.177596 
                   
                   
                   
                 AF218002 
                 No 
               
               
                 79 
                 Hs.848 
                 FKBP4 
                 2288 
                 600611 
                 NM_002014 
                 No 
               
               
                 80 
                 Hs.77060 
                 PSMB6 
                 5694 
                 600307 
                 BC000835 
                 No 
               
               
                 81 
                 Hs.75777 
                 TAGLN 
                 6876 
                 600818 
                 NM_003186 
                 No 
               
               
                 82 
                 Hs.278569 
                 SNX17 
                 9784 
                 605963 
                 NM_014748 
                 No 
               
               
                 83 
                 Hs.105584 
                 RPS6KA4 
                 8986 
                 603606 
                 NM_003942 
                 No 
               
               
                 84 
                 Hs.139648 
                 KIF1C 
                 10749  
                 603060 
                 AB014606 
                 No 
               
               
                 85 
                 Hs.25817 
                   
                   
                   
                 NM_017797 
                 No 
               
               
                 86 
                 Hs.77890 
                 GUCY1B3 
                 2983 
                 139397 
                 NM_000857 
                 No 
               
               
                 87 
                 Hs.79137 
                 PCMT1 
                 5110 
                 176851 
                 NM_005389 
                 No 
               
               
                 88 
                 Hs.174441 
                 DDO 
                 8528 
                 124450 
                 NM_003649 
                 No 
               
               
                 89 
                 Hs.18075 
                   
                   
                   
                 NM_032823 
                 No 
               
               
                 90 
                 Hs.183601 
                 RGS16 
                 6004 
                 602514 
                 NM_002928 
                 No 
               
               
                 91 
                 Hs.7381 
                 VDAC3 
                 7419 
                   
                 BC002456 
                 No 
               
               
                 92 
                 Hs.197298 
                 NS1 
                 10625  
                   
                 AF205218 
                 No 
               
               
                 93 
                 Hs.82316 
                 MTAP44 
                 10561  
                   
                 NM_006417 
                 No 
               
               
                 94 
                 Hs.155097 
                 CA2 
                  760 
                 259730 
                 NM_000067 
                 No 
               
               
                 95 
                 Hs.171734 
                 PPP2R5C 
                 5527 
                 601645 
                 NM_002719 
                 No 
               
               
                 96 
                 Hs.204041 
                   
                   
                   
                 NM_012111 
                 No 
               
               
                 97 
                 Hs.151777 
                 EIF2S1 
                 1965 
                 603907 
                 BC002513 
                 No 
               
               
                 98 
                 Hs.138860 
                 ARHGAP1 
                  392 
                 602732 
                 BC018118 
                 No 
               
               
                 99 
                 Hs.156764 
                 RAP1B 
                 5908 
                 179530 
                 NM_015646 
                 No 
               
               
                 100  
                 Hs.75721 
                 PFN1 
                 5216 
                 176610 
                 NM_005022 
                 No 
               
               
                 101  
                 Hs.43658 
                   
                   
                   
                 AL050137 
                 No 
               
               
                 102  
                 Hs.11197 
                   
                   
                   
                 BC000628 
                 No 
               
               
                 103  
                 Hs.6361 
                   
                   
                   
                 NM_021970 
                 No 
               
               
                 104  
                 Hs.169965 
                 CHN1 
                 1123 
                 118423 
                 NM_001822 
                 No 
               
               
                 105  
                 Hs.31720 
                 HEPH 
                 9843 
                 300167 
                 NM_014799 
                 No 
               
               
                 106  
                 Hs.8294 
                   
                   
                   
                 NM_014846 
                 No 
               
               
                 107  
                 Hs.279869 
                 MAAT1 
                 10573  
                 604853 
                 NM_006428 
                 No 
               
               
                 108  
                 Hs.205736 
                 HKE2 
                 10471  
                 605660 
                 NM_014260 
                 No 
               
               
                 109  
                 Hs.81182 
                 HNMT 
                 3176 
                 605238 
                 NM_006895 
                 No 
               
               
                 110  
                 Hs.260238 
                   
                   
                   
                 NM_018238 
                 No 
               
               
                 111  
                 Hs.239489 
                 TIA1 
                 7072 
                 603518 
                 NM_022173 
                 No 
               
               
                 112  
                 Hs.78223 
                 APEH 
                  327 
                 102645 
                 NM_001640 
                 No 
               
               
                 113  
                 Hs.287797 
                 ITGB1 
                 3688 
                 135630 
                 AK024451 
                 No 
               
               
                 114  
                 Hs.169474 
                 EIF2B4 
                 8890 
                   
                 NM_015636 
                 No 
               
               
                 115  
                 Hs.24756 
                 HGS 
                 9146 
                 604375 
                 NM_004712 
                 No 
               
               
                 116  
                 Hs.75256 
                 RGS1 
                 5996 
                 600323 
                 NM_002922 
                 No 
               
               
                 117  
                 Hs.118065 
                 PSMB7 
                 5695 
                 604030 
                 NM_002799 
                 No 
               
               
                 118  
                 Hs.86392 
                   
                   
                   
                 AB037823 
                 Yes 
               
               
                 119  
                 Hs.1940 
                 CRYAB 
                 1410 
                 123590 
                 NM_001885 
                 No 
               
               
                 120  
                 Hs.78793 
                 PRKCZ 
                 5590 
                 176982 
                 NM_002744 
                 No 
               
               
                 121  
                 Hs.286241 
                 PRKAR2A 
                 5576 
                 176910 
                 BC002763 
                 No 
               
               
                 122  
                 Hs.169780 
                   
                   
                   
                 NM_006545 
                 No 
               
               
                 123  
                 Hs.278426 
                 PDAP1 
                 11333  
                   
                 NM_014891 
                 No 
               
               
                   
               
             
          
         
       
     
         [0025]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                   
               
               
                 Additional colon extracellular and cytoplasmic tumor endothelial 
               
               
                 markers 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Hs.108850 
                 intestinal cell kinase 
                 Protein Kinase 
               
               
                 Hs.155418 
                 GS3955 protein 
                 Protein Kinase 
               
               
                 Hs.153937 
                 activated p21cdc42Hs kinase 
                 Protein Kinase 
               
               
                 Hs. 17820 
                 Rho-associated, coiled-coil- 
                 Protein Kinase 
               
               
                   
                 containing protein kinase I 
               
               
                 Hs.9587 
                 KIAA2002 protein 
                 Protein Kinase 
               
               
                 Hs.47061 
                 unc-51-like kinase 1 
                 Protein Kinase 
               
               
                 Hs.2463 
                 angiopoietin 1 
                 Extracellular Growth 
               
               
                   
                   
                 Factors &amp; Cytokine 
               
               
                 Hs.37040 
                 PDGF alpha polypeptide 
                 Extracellular Growth 
               
               
                   
                   
                 Factors &amp; Cytokine 
               
               
                 Hs.235935 
                 insulin-like growth factor 
                 Extracellular Growth 
               
               
                   
                 binding protein 
                 Factors &amp; Cytokine 
               
               
                   
               
             
          
         
       
     
         [0026]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                   
               
               
                 Extracellular Colon Tumor Endothelial Markers 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.101302 
                 TEM36, COL12A1 
                 120320 
                 NP_004361 
               
               
                 Hs.108623 
                 thrombospondin 2 
                 188061 
                 NP_003238 
               
               
                 Hs.108885 
                 collagen, type VI, alpha 1 
                 120220 
                 NP_001839 
               
               
                 Hs.1103 
                 transforming growth factor, beta 
                 190180 
                 NP_000651 
               
               
                   
                 1 (Camurati-Engelmann 
               
               
                   
                 disease) 
               
               
                 Hs.111301 
                 TEM7, matrix metalloproteinase 
                 120360 
                 NP_004521 
               
               
                   
                 2 (gelatinase A, 72kD 
               
               
                   
                 gelatinase, 72kD type IV 
               
               
                   
                 collagenase) 
               
               
                 Hs.111779 
                 secreted protein, acidic, 
                 182120 
                 NP_003109 
               
               
                   
                 cysteine-rich (osteonectin) 
               
               
                 Hs.118397 
                 AE binding protein 1 
                 602981 
                 NP_001120 
               
               
                 Hs.118787 
                 transforming growth factor, 
                 601692 
                 NP_000349 
               
               
                   
                 beta-induced, 68kDa 
               
               
                 Hs.119129 
                 TEM31, COL4A1 rev str; 
                 120130 
                 NP_001836 
               
               
                 Hs.1192O6 
                 insulin-like growth factor 
                 602867 
                 NP_001544 
               
               
                   
                 binding protein 7 
               
               
                 Hs.119571 
                 collagen, type III, alpha 1 
                 120180 
                 NP_000081 
               
               
                   
                 (Ehlers-Danlos syndrome type 
               
               
                   
                 IV, autosomal dominant) 
               
               
                 Hs.1274 
                 TEM25, BMP1; transcript 
                 112264 
                 NP_006120 
               
               
                   
                 variants were checked, BMP1-3 
               
               
                   
                 corresponds to tag, 
               
               
                   
                 metalloproteinase, capable of 
               
               
                   
                 inducing formation of cartilage 
               
               
                 Hs.1279 
                 complement component 1, r 
                 216950 
                 NP_001724 
               
               
                   
                 subcomponent 
               
               
                 Hs.146428 
                 collagen, type V, alpha 1 
                 120215 
                 NP_000084 
               
               
                 Hs.151242 
                 serine (or cysteine) proteinase 
                 606860 
                 NP_000053 
               
               
                   
                 inhibitor, clade G (C1 
               
               
                   
                 inhibitor), member 1, 
               
               
                   
                 (angioedema, hereditary) 
               
               
                 Hs.151738 
                 (matrix metalloproteinase 9 
                 120361 
                 NP_004985 
               
               
                   
                 (gelatinase B, 92kDa gelatinase, 
               
               
                   
                 92kDa type IV collagenase) 
               
               
                 Hs.153684 
                 frizzled-related protein 
                 605083 
                 NP_001454 
               
               
                 Hs.155324 
                 TEM6, stromelysin; cleaves 
                 185261 
                 NP_005931 
               
               
                   
                 collagen, involved in tissue 
               
               
                   
                 remodeling, migration; 
               
               
                   
                 knockouts don&#39;t support tumor 
               
               
                   
                 growth or metastasis as well as 
               
               
                   
                 wild-type mice 
               
               
                 Hs.157211 
                 C1q and tumor necrosis factor 
                   
                 NP_056460 
               
               
                   
                 related protein 5 
               
               
                 Hs.159263 
                 collagen, type VI, alpha 2 
                 120240 
                 NP_001840 
               
               
                 Hs.1640 
                 collagen, type VII, alpha 1 
                 120120 
                 NP_000085 
               
               
                   
                 (epidermolysis bullosa, 
               
               
                   
                 dystrophic, dominant and 
               
               
                   
                 recessive) 
               
               
                 Hs.169756 
                 complement component 1, s 
                 120580 
                 NP_001725 
               
               
                   
                 subcomponent 
               
               
                 Hs.17144 
                 short-chain 
                   
                 NP_004744 
               
               
                   
                 dehydrogenase/reductase 1 
               
               
                 Hs.172928 
                 TEM23, COL1A1 rev str; 
                 120150 
                 NP_000079 
               
               
                   
                 claimed as no match 
               
               
                 Hs.173594 
                 serine (or cysteine) proteinase 
                 172860 
                 NP_002606 
               
               
                   
                 inhibitor, clade F (alpha-2 
               
               
                   
                 antiplasmin, pigment epithelium 
               
               
                   
                 derived factor), member 1 
               
               
                 Hs.179573 
                 TEM10, COL1A2 involved in 
                 120160 
                 NP_000080 
               
               
                   
                 tissue remodeling 
               
               
                 Hs.272688 
                 hypothetical protein FLJ20397 
                   
                 NP_060272 
               
               
                 Hs.287820 
                 fibronectin 1 
                 135600 
                 NP_002017 
               
               
                 Hs.288126 
                 spondin 2, extracellular matrix 
                 605918 
                 BAB15789 
               
               
                   
                 protein 
               
               
                 Hs.296267 
                 follistatin-like 1 
                 605547 
                 NP_009016 
               
               
                 Hs.4909 
                 TEM4, DKK-3 involved in 
                 605416 
                 NP_037385 
               
               
                   
                 regulation of Wnt signaling 
               
               
                   
                 pathway 
               
               
                 Hs.57929 
                 TEM27, slit homolog 3 involved 
                 603745 
                 BAA32466 
               
               
                   
                 in cell adhesion 
               
               
                 Hs.5831 
                 tissue inhibitor of 
                 305370 
                 NP_003245 
               
               
                   
                 metalloproteinase 1 (erythroid 
               
               
                   
                 potentiating activity, collagenase 
               
               
                   
                 inhibitor) 
               
               
                 Hs.699 
                 peptidylprolyl isomerase B 
                 123841 
                 NP_000933 
               
               
                   
                 (cyclophilin B) 
               
               
                 Hs.202097 
                 procollagen C-endopeptidase 
                 600270 
                 NP_002584 
               
               
                   
                 enhancer 
               
               
                 Hs.230 
                 fibromodulin 
                 600245 
                 NP_002014 
               
               
                 Hs.241575 
                 hypothetical protein CAB56184 
                   
                 NP_115909 
               
               
                 Hs.356624 
                 TEM11, nidogen (enactin) 
                 131390 
                 NP_002499 
               
               
                 Hs.375599 
                 immunoglobulin lambda joining 
               
               
                   
                 3 
               
               
                 Hs.40098 
                 cysteine knot superfamily 1, 
                 603054 
                 NP_037504 
               
               
                   
                 BMP antagonist 1 
               
               
                 Hs.418 
                 fibroblast activation protein, 
                 600403 
                 NP_004451 
               
               
                   
                 alpha 
               
               
                 Hs.72157 
                 adlican 
                   
                 NP_056234 
               
               
                 Hs.750 
                 fibrillin 1 (Marfan syndrome) 
                 134797 
                 NP_000129 
               
               
                 Hs.75410 
                 heat shock 70kDa protein 5 
                 138120 
                 NP_005338 
               
               
                   
                 (glucose-regulated protein, 
               
               
                   
                 78kDa) 
               
               
                 Hs.75617 
                 collagen, type IV, alpha 2 
                 120090 
                 NP_001837 
               
               
                 Hs.76152 
                 decorin 
                 125255 
                 NP_001911 
               
               
                 Hs.77274 
                 plasminogen activator, urokinase 
                 191840 
                 NP_002649 
               
               
                 Hs.78409 
                 collagen, type XVIII, alpha 1 
                 120328 
                 NP_085059 
               
               
                 Hs.78672 
                 laminin, alpha 4 
                 600133 
                 NP_002281 
               
               
                 Hs.79222 
                 galactosidase, beta 1 
                 230500 
                 NP_000395 
               
               
                 Hs.79732 
                 fibulin 1 
                 135820 
                 NP_006476 
               
               
                 Hs.79914 
                 TEM37, lumican; ECM 
                 600616 
                 NP_002336 
               
               
                   
                 proteoglycan 
               
               
                 Hs.80988 
                 TEM12, COL6A3 involved in 
                 120250 
                 NP_004360 
               
               
                   
                 tissue remodeling 
               
               
                 Hs.82045 
                 midkine (neurite growth- 
                 162096 
                 NP_002382 
               
               
                   
                 promoting factor 2) 
               
               
                 Hs.821 
                 biglycan 
                 301870 
                 NP_001702 
               
               
                 Hs.82124 
                 laminin, beta 1 
                 150240 
                 NP_002282 
               
               
                 Hs.82985 
                 collagen, type V, alpha 2 
                 120190 
                 NP_000384 
               
               
                 Hs.83354 
                 lysyl oxidase-like 2 
                 606663 
                 NP_002309 
               
               
                 Hs.83551 
                 microfibrillar-associated protein 
                 156790 
                 NP_059453 
               
               
                   
                 2 
               
               
                 Hs.86392 
                 KIAA1402 protein 
                   
                 BAA92640 
               
               
                 Hs.8867 
                 cysteine-rich, angiogenic 
                 602369 
                 NP_001545 
               
               
                   
                 inducer, 61 
               
               
                 Hs.9383 
                 cysteine-rich with EGF-like 
                 607170 
                 NP_056328 
               
               
                   
                 domains 1 
               
               
                 Hs.94037 
                 hypothetical protein FLJ23053 
                   
                 NP_075058 
               
               
                 Hs.94795 
                 TEM41, homology to secreted 
                   
                 BAB84990 
               
               
                   
                 protein myocilin (olfactomedin) 
               
               
                   
                 domain) submit predicted 
               
               
                   
                 sequence 
               
               
                   
               
             
          
         
       
     
         [0027]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                   
               
               
                 Cytoplasmic Colon Tumor Endothelial Markers 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.10098 
                 putative nucleolar RNA helicase 
                   
                 NP_061955 
               
               
                 Hs.10558 
                 ribosomal protein S6 kinase, 
                 603606 
                 NP_003933 
               
               
                 4 
                 90kDa, polypeptide 4 
               
               
                 Hs.11197 
                 chromosome 20 open reading 
               
               
                   
                 frame 92 
               
               
                 Hs.11806 
                 proteasome (prosome, 
                 604030 
               
               
                 5 
                 macropain) subunit, beta type, 7 
               
               
                 Hs.11824 
                 ADP-ribosylation factor guanine 
                 605371 
                 NP_006411 
               
               
                 9 
                 nucleotide-exchange factor 2 
               
               
                   
                 (brefeldin A-inhibited) 
               
               
                 Hs.1197 
                 heat shock 10kDa protein 1 
                 600141 
                 NP_002148 
               
               
                   
                 (chaperonin 10) 
               
               
                 Hs.15177 
                 eukaryotic translation initiation 
                 603907 
                 NP_004085 
               
               
                 7 
                 factor 2, subunit 1 alpha, 35kDa 
               
               
                 Hs.15509 
                 carbonic anhydrase II 
                 259730 
                 NP_000058 
               
               
                 7 
               
               
                 Hs.17270 
                 folliculin 
                 607273 
                 NP_659434 
               
               
                 2 
               
               
                 Hs.17391 
                 eukaryotic translation initiation 
                 601102 
                 NP_001958 
               
               
                 2 
                 factor 4A, isoform 2 
               
               
                 Hs.26023 
                 hypothetical protein FLJ10842 
                   
                 NP_060708 
               
               
                 8 
               
               
                 Hs.27856 
                 sorting nexin 17 
                 605963 
                 NP_055563 
               
               
                 9 
               
               
                 Hs.27977 
                 brain specific protein 
                   
                 NP_057224 
               
               
                 2 
               
               
                 Hs.27986 
                 mitochondrial ribosomal protein 
                 604853 
               
               
                 9 
                 L28 
               
               
                 Hs.29341 
                 chromosome 20 open reading 
                   
                 NP_073597 
               
               
                   
                 frame 81 
               
               
                 Hs.3O244 
                 vacuolar protein sorting 16 
                   
                 NP_072097 
               
               
                 1 
                 (yeast) 
               
               
                 Hs.31505 
                 hypothetical protein MGC15875 
                   
                 NP_699204 
               
               
                 4 
               
               
                 Hs.3268 
                 heat shock 70kDa protein 6 
                 140555 
                 NP_002146 
               
               
                   
                 (HSP70B′) 
               
               
                 Hs.32741 
                 TEM15, COL3A1, Homo 
               
               
                 2 
                 sapiens clone FLC1492 
               
               
                   
                 PRO3121 mRNA, complete cds 
               
               
                 Hs.33479 
                 hypothetical protein FLJ14675 
                   
                 NP_116212 
               
               
                 0 
               
               
                 Hs.35143 
                 TEM24, tensin 
                 600076 
                 NP_072174 
               
               
                 2 
               
               
                 Hs.43658 
                 DKFZP586L151 protein 
                   
                 CAB43286 
               
               
                 Hs.5120 
                 dynein, cytoplasmic, light 
                 601562 
                 NP_003737 
               
               
                   
                 polypeptide 1 
               
               
                 Hs.57813 
                 zinc ribbon domain containing, 
                 607525 
                 NP_055411 
               
               
                   
                 1 
               
               
                 Hs.6361 
                 mitogen-activated protein 
                 603296 
               
               
                   
                 kinase kinase 1 interacting 
               
               
                   
                 protein 1 
               
               
                 Hs.19818 
                 TEM21, DKFZp434G162 
                   
                 CAB82400 
               
               
                 2 
               
               
                 Hs.22775 
                 lectin, galactoside-binding, 
                 150570 
                 NP_002296 
               
               
                 1 
                 soluble, 1 (galectin 1) 
               
               
                 Hs.23975 
                 nuclear receptor subfamily 2, 
                 132880 
                 NP_005225 
               
               
                 2 
                 group F, member 6 
               
               
                 Hs.35320 
                 solute carrier family 26, 
                   
                 NP_597996 
               
               
                 7 
                 member 10 
               
               
                 Hs.35613 
                 homologous to yeast nitrogen 
                 607072 
                 NP_006536 
               
               
                 7 
                 permease (candidate tumor 
               
               
                   
                 suppressor) 
               
               
                 Hs.36927 
                 heat shock 105kD 
                   
                 NP_006635 
               
               
                 Hs.75721 
                 profilin 1 
                 176610 
                 NP_005013 
               
               
                 Hs.75777 
                 transgelin 
                 600818 
                 NP_003177 
               
               
                 Hs.76853 
                 DnaJ (Hsp40) homolog, 
               
               
                   
                 subfamily A, member 4 
               
               
                 Hs.77060 
                 proteasome (prosome, 
                 600307 
                 NP_002789 
               
               
                   
                 macropain) subunit, beta type, 6 
               
               
                 Hs.77890 
                 guanylate cyclase 1, soluble, 
                 139397 
                 NP_000848 
               
               
                   
                 beta 3 
               
               
                 Hs.79137 
                 protein-L-isoaspartate (D- 
                 176851 
                 NP_005380 
               
               
                   
                 aspartate) O-methyltransferase 
               
               
                 Hs.81182 
                 histamine N-methyltransferase 
                 605238 
                 NP_008826 
               
               
                 Hs.82316 
                 interferon-induced protein 44 
                   
                 NP_006408 
               
               
                 Hs.82646 
                 DnaJ (Hsp40) homolog, 
                 604572 
                 NP_006136 
               
               
                   
                 subfmaily B, member 1 
               
               
                 Hs.848 
                 FK506 binding protein 4, 59kDa 
                 600611 
                 NP_002005 
               
               
                 Hs.8997 
                 heat shock 70kDa protein 1A 
                 140550 
                 NP_005336 
               
               
                   
               
             
          
         
       
     
         [0028]     It is clear that normal and tumor endothelium are highly related, sharing many endothelial cell specific markers. It is equally clear that the endothelium derived from tumors is qualitatively different from that derived from normal tissues of the same type and is also different from primary endothelial cultures. These genes are characteristically expressed in tumors derived from several different tissue types, documenting that tumor endothelium, in general, is different from normal endothelium. The genes expressed differentially in tumor endothelium are also expressed during other angiogenic processes such as corpus luteum formation and wound healing. It is therefore more appropriate to regard the formation of new vessels in tumors as “neoangiogenesis” rather than “tumor angiogenesis” per se. This distinction is important from a variety of perspectives, and is consistent with the idea that tumors recruit vasculature using much of, or basically the same signals elaborated during other physiologic or pathological processes. That tumors represent “unhealed wounds” is one of the oldest ideas in cancer biology.  
         [0029]     Isolated and purified nucleic acids, according to the present invention are those which are not linked to those genes to which they are linked in the human genome. Moreover, they are not present in a mixture such as a library containing a multitude of distinct sequences from distinct genes. They may be, however, linked to other genes such as vector sequences or sequences of other genes to which they are not naturally adjacent. Tags disclosed herein, because of the way that they were made, represent sequences which are 3′ of the 3′ most restriction enzyme recognition site for the tagging enzyme used to generate the SAGE tags. In this case, the tags are 3′ of the most 3′ most NlaIII site in the cDNA molecules corresponding to mRNA. Nucleic acids corresponding to tags may be RNA, cDNA, or genomic DNA, for example. Such corresponding nucleic acids can be determined by comparison to sequence databases to determine sequence identities. Sequence comparisons can be done using any available technique, such as BLAST, available from the National Library of Medicine, National Center for Biotechnology Information. Tags can also be used as hybridization probes to libraries of genomic or cDNA to identify the genes from which they derive. Thus, using sequence comparisons or cloning, or combinations of these methods, one skilled in the art can obtain full-length nucleic acid sequences. Genes corresponding to tags will contain the sequence of the tag at the 3′ end of the coding sequence or of the 3′ untranslated region (UTR), 3′ of the 3′ most recognition site in the cDNA for the restriction endonuclease which was used to make the tags. The nucleic acids may represent either the sense or the anti-sense strand. Nucleic acids and proteins althought disclosed herein with sequence particularity, may be derived from a single individual. Allelic variants which occur in the population of humans are including within the scope of such nucleic acids and proteins. Those of skill in the art are well able to identify allelic variants as being the same gene or protein. Given a nucleic acid, one of ordinary skill in the art can readily determine an open reading frame present, and consequently the sequence of a polypeptide encoded by the open reading frame and, using techniques well known in the art, express such protein in a suitable host. Proteins comprising such polypeptides can be the naturally occurring proteins, fusion proteins comprising exogenous sequences from other genes from humans or other species, epitope tagged polypeptides, etc. Isolated and purified proteins are not in a cell, and are separated from the normal cellular constituents, such as nucleic acids, lipids, etc. Typically the protein is purified to such an extent that it comprises the predominant species of protein in the composition, such as greater than 50, 60 70, 80, 90, or even 95% of the proteins present.  
         [0030]     Using the proteins according to the invention, one of ordinary skill in the art can readily generate antibodies which specifically bind to the proteins. Such antibodies can be monoclonal or polyclonal. They can be chimeric, humanized, or totally human. Any functional fragment or derivative of an antibody can be used including Fab, Fab′, Fab2, Fab′2, and single chain variable regions. So long as the fragment or derivative retains specificity of binding for the endothelial marker protein it can be used. Antibodies can be tested for specificity of binding by comparing binding to appropriate antigen to binding to irrelevant antigen or antigen mixture under a given set of conditions. If the antibody binds to the appropriate antigen at least 2, 5, 7, and preferably 10 times more than to irrelevant antigen or antigen mixture then it is considered to be specific.  
         [0031]     Techniques for making such partially to fully human antibodies are known in the art and any such techniques can be used. According to one particularly preferred embodiment, fully human antibody sequences are made in a transgenic mouse which has been engineered to express human heavy and light chain antibody genes. Multiple strains of such transgenic mice have been made which can produce different classes of antibodies. B cells from transgenic mice which are producing a desirable antibody can be fused to make hybridoma cell lines for continuous production of the desired antibody. See for example, Nina D. Russel, Jose R. F. Corvalan, Michael L. Gallo, C. Geoffrey Davis, Liise-Anne Pirofski. Production of Protective Human Antipneumococcal Antibodies by Transgenic Mice with Human Immunoglobulin Loci  Infection and Immunity  April 2000, p. 1820-1826; Michael L. Gallo, Vladimir E. Ivanov, Aya Jakobovits, and C. Geoffrey Davis. The human immunoglobulin loci introduced into mice: V (D) and J gene segment usage similar to that of adult humans  European Journal of Immunology  30: 534-540, 2000; Larry L. Green. Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies  Journal of Immunological Methods  231 11-23, 1999; Yang X-D, Corvalan J R F, Wang P, Roy CM-N and Davis C G. Fully Human Anti-interleukin-8 Monoclonal Antibodies: Potential Therapeutics for the Treatment of Inflammatory Disease States.  Journal of Leukocyte Biology  Vol. 66, pp 401-410 (1999); Yang X-D, Jia X-C, Corvalan J R F, Wang P, C G Davis and Jakobovits A. Eradication of Established Tumors by a Fully Human Monoclonal Antibody to the Epidermal Growth Factor Receptor without Concomitant Chemotherapy.  Cancer Research  Vol. 59, Number 6, pp 1236-1243 (1999); Jakobovits A. Production and selection of antigen-specific fully human monoclonal antibodies from mice engineered with human Ig loci.  Advanced Drug Delivery Reviews  Vol. 31, pp: 33-42 (1998); Green L and Jakobovits A. Regulation of B cell development by variable gene complexity in mice reconstituted with human immunoglobulin yeast artificial chromosomes.  J. Exp. Med . Vol. 188, Number 3, pp: 483-495 (1998); Jakobovits A. The long-awaited magic bullets: therapeutic human monoclonal antibodies from transgenic mice.  Exp. Opin. Invest. Drugs  Vol. 7(4), pp: 607-614 (1998); Tsuda H, Maynard-Currie K, Reid L, Yoshida T, Edamura K, Maeda N, Smithies O, Jakobovits A. Inactivation of Mouse HPRT locus by a 203-bp retrotransposon insertion and a 55-kb gene-targeted deletion: establishment of new HPRT-Deficient mouse embryonic stem cell lines.  Genomics  Vol. 42, pp: 413421 (1997); Sherman-Gold, R. Monoclonal Antibodies: The Evolution from &#39;80s Magic Bullets To Mature, Mainstream Applications as Clinical Therapeutics.  Genetic Engineering News  Vol. 17, Number 14 (August 1997); Mendez M, Green L, Corvalan J, Jia X-C, Maynard-Currie C, Yang X-d, Gallo M, Louie D, Lee D, Erickson K, Luna J, Roy C, Abderrahim H, Kirschenbaum F, Noguchi M, Smith D, Fukushima A, Hales J, Finer M, Davis C, Zsebo K, Jakobovits A. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice.  Nature Genetics  Vol. 15, pp: 146-156 (1997); Jakobovits A. Mice engineered with human immunoglobulin YACs: A new technology for production of fully human antibodies for autoimmunity therapy.  Weir&#39;s Handbook of Experimental Immunology, The Integrated Immune System  Vol. IV, pp: 194.1-194.7 (1996); Jakobovits A. Production of fully human antibodies by transgenic mice.  Current Opinion in Biotechnology  Vol. 6, No. 5, pp: 561-566 (1995); Mendez M, Abderrahim H, Noguchi M, David N, Hardy M, Green L, Tsuda H, Yoast S, Maynard-Currie C, Garza D, Gemmill R, Jakobovits A, Klapholz S. Analysis of the structural integrity of YACs comprising human immunoglobulin genes in yeast and in embryonic stem cells.  Genomics  Vol. 26, pp: 294-307 (1995); Jakobovits A. YAC Vectors: Humanizing the mouse genome.  Current Biology  Vol. 4, No. 8, pp: 761-763 (1994); Arbones M, Ord D, Ley K, Ratech H, Maynard-Curry K, Otten G, Capon D, Tedder T. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice.  Immunity  Vol. 1, No. 4, pp: 247-260 (1994); Green L, Hardy M, Maynard-Curry K, Tsuda H, Louie D, Mendez M, Abderrahim H, Noguchi M, Smith D, Zeng Y, et. al. Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs.  Nature Genetics  Vol. 7, No. 1, pp: 13-21 (1994); Jakobovits A, Moore A, Green L, Vergara G, Maynard-Curry K, Austin H, Klapholz S. Germ-line transmission and expression of a human-derived yeast artificial chromosome.  Nature  Vol. 362, No. 6417, pp: 255-258 (1993); Jakobovits A, Vergara G, Kennedy J, Hales J, McGuinness R, Casentini-Borocz D, Brenner D, Otten G. Analysis of homozygous mutant chimeric mice: deletion of the immunoglobulin heavy-chain joining region blocks B-cell development and antibody production.  Proceedings of the National Academy of Sciences USA  Vol. 90, No. 6, pp: 2551-2555 (1993); Kucherlapati et al., U.S. Pat. No. 6,1075,181.  
         [0032]     Antibodies can also be made using phage display techniques. Such techniques can be used to isolate an initial antibody or to generate variants with altered specificity or avidity characteristics. Single chain Fv can also be used as is convenient. They can be made from vaccinated transgenic mice, if desired. Antibodies can be produced in cell culture, in phage, or in various animals, including but not limited to cows, rabbits, goats, mice, rats, hamsters, guinea pigs, sheep, dogs, cats, monkeys, chimpanzees, apes.  
         [0033]     Antibodies can be labeled with a detectable moiety such as a radioactive atom, a chromophore, a fluorophore, or the like. Such labeled antibodies can be used for diagnostic techniques, either in vivo, or in an isolated test sample. Antibodies can also be conjugated, for example, to a pharmaceutical agent, such as chemotherapeutic drug or a toxin. They can be linked to a cytokine, to a ligand, to another antibody. Suitable agents for coupling to antibodies to achieve an anti-tumor effect include cytokines, such as interleukin 2 (IL-2) and Tumor Necrosis Factor (TNF); photosensitizers, for use in photodynamic therapy, including aluminum (III) phthalocyanine tetrasulfonate, hematoporphyrin, and phthalocyanine; radionuclides, such as iodine-131 ( 131 I), yttrium-90 ( 90 Y), bismuth-212 ( 212 Bi), bismuth-213 ( 213 Bi), technetium-99m ( 99m Tc), rhenium-186 ( 186 Re), and rhenium-188 ( 188 Re); antibiotics, such as doxorubicin, adriamycin, daunorubicin, methotrexate, daunomycin, neocarzinostatin, and carboplatin; bacterial, plant, and other toxins, such as diphtheria toxin, pseudomonas exotoxin A, staphylococcal enterotoxin A, abrin-A toxin, ricin A (deglycosylated ricin A and native ricin A), TGF-alpha toxin, cytotoxin from chinese cobra (naja naja atra), and gelonin (a plant toxin); ribosome inactivating proteins from plants, bacteria and fungi, such as restrictocin (a ribosome inactivating protein produced by  Aspergillus restrictus ), saporin (a ribosome inactivating protein from  Saponaria officinalis ), and RNase; tyrosine kinase inhibitors; ly207702 (a difluorinated purine nucleoside); liposomes containing antitumor agents (e.g., antisense oligonucleotides, plasmids which encode for toxins, methotrexate, etc.); and other antibodies or antibody fragments, such as F(ab).  
         [0034]     Those of skill in the art will readily understand and be able to make such antibody derivatives, as they are well known in the art. The antibodies may be cytotoxic on their own, or they may be used to deliver cytotoxic agents to particular locations in the body. The antibodies can be administered to individuals in need thereof as a form of passive immunization.  
         [0035]     Characterization of extracellular regions for cell surface and secreted proteins from the protein sequence can be based on the prediction of signal sequence, transmembrane domains and functional domains. Antibodies are preferably specifically immunoreactive with membrane associated proteins, particularly to extracellular domains of such proteins or to secreted proteins. Such targets are readily accessible to antibodies, which typically do not have access to the interior of cells or nuclei. However, in some applications, antibodies directed to intracellular proteins may be useful as well. Moreover, for diagnostic purposes, an intracellular protein may be an equally good target since cell lysates may be used rather than a whole cell assay.  
         [0036]     Computer programs can be used to identify extracellular domains of proteins whose sequences are known. Such programs include SMART software (Schultz et al., Proc. Natl. Acad. Sci. USA 95: 5857-5864, 1998) and Pfam software (Bateman et al., Nucleic acids Res. 28: 263-266, 2000) as well as PSORTII. Typically such programs identify transmembrane domains; the extracellular domains are identified as immediately adjacent to the transmembrane domains. Prediction of extracellular regions and the signal cleavage sites are only approximate. It may have a margin of error + or −5 residues. Signal sequence can be predicted using three different methods (Nielsen et al,  Protein Engineering  10: 1-6, 1997, Jagla et. al, Bioinformatics 16: 245-250, 2000, Nakai, K and Horton, P. Trends in Biochem. Sci. 24:34-35, 1999) for greater accuracy. Similarly transmembrane (TM) domains can be identified by multiple prediction methods. (Pasquier, et. al, Protein Eng. 12:381-385, 1999, Sonnhammer et al., In Proc. of Sixth Int. Conf. on Intelligent Systems for Molecular Biology, p. 175-182, Ed J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D. Sankoff, and C. Sensen Menlo Park, Calif.: AAAI Press, 1998, Klein, et. al, Biochim. Biophys. Acta, 815:468, 1985, Nakai and Kanehisa Genomics, 14: 897-911, 1992). In ambiguous cases, locations of functional domains in well characterized proteins are used as a guide to assign a cellular localization.  
         [0037]     Putative functions or functional domains of novel proteins can be inferred from homologous regions in the database identified by BLAST searches (Altschul et. al. Nucleic Acid Res. 25: 3389-3402, 1997) and/or from a conserved domain database such as Pfam (Bateman et. al, Nucleic Acids Res. 27:260-262 1999) BLOCKS (Henikoff, et. al, Nucl. Acids Res. 28:228-230, 2000) and SMART (Ponting, et. al, Nucleic Acid Res. 27,229-232, 1999). Extracellular domains include regions adjacent to a transmembrane domain in a single transmembrane domain protein (out-in or type I class). For multiple transmembrane domains proteins, the extracellular domain also includes those regions between two adjacent transmembrane domains (in-out and out-in). For type II transmembrane domain proteins, for which the N-terminal region is cytoplasmic, regions following the transmembrane domain is generally extracellular. Secreted proteins on the other hand do not have a transmembrane domain and hence the whole protein is considered as extracellular.  
         [0038]     Membrane associated proteins can be engineered to delete the transmembrane domains, thus leaving the extracellular portions which can bind to ligands. Such soluble forms of transmembrane receptor proteins can be used to compete with natural forms for binding to ligand. Thus such soluble forms act as inhibitors. and can be used therapeutically as anti-angiogenic agents, as diagnostic tools for the quantification of natural ligands, and in assays for the identification of small molecules which modulate or mimic the activity of a TEM:ligand complex.  
         [0039]     Alternatively, the endothelial markers themselves can be used as vaccines to raise an immune response in the vaccinated animal or human. For such uses, a protein, or immunogenic fragment of such protein, corresponding to the intracellular, extracellular or secreted TEM of interest is administered to a subject. The immogenic agent may be provided as a purified preparation or in an appropriately expressing cell. The administration may be direct, by the delivery of the immunogenic agent to the subject, or indirect, through the delivery of a nucleic acid encoding the immunogenic agent under conditions resulting in the expression of the immunogenic agent of interest in the subject. The TEM of interest may be delivered in an expressing cell, such as a purified population of tumor endothelial cells or a populations of fused tumor endothelial and dendritic cells. Nucleic acids encoding the TEM of interest may be delivered in a viral or non-viral delivery vector or vehicle. Non-human sequences encoding the human TEM of interest or other mammalian homolog can be used to induce the desired immunologic response in a human subject. For several of the TEMs of the present invention, mouse, rat or other ortholog sequences are described herein or can be obtained from the literature or using techniques well within the skill of the art.  
         [0040]     Endothelial cells can be identified using the markers which are disclosed herein as being endothelial cell specific. These include the human markers identified by SEQ ID NOS: 1-123, i.e., the normal, pan-endothelial, and the tumor endothelial markers. Antibodies specific for such markers can be used to identify such cells, by contacting the antibodies with a population of cells containing some endothelial cells. The presence of cross-reactive material with the antibodies identifies particular cells as endothelial. Similarly, lysates of cells can be tested for the presence of cross-reactive material. Any known format or technique for detecting cross-reactive material can be used including, immunoblots, radioimmunoassay, ELISA, immunoprecipitation, and immunohistochemistry. In addition, nucleic acid probes for these markers can also be used to identify endothelial cells. Any hybridization technique known in the art including Northern blotting, RT-PCR, microarray hybridization, and in situ hybridization can be used.  
         [0041]     One can identify tumor endothelial cells for diagnostic purposes, testing cells suspected of containing one or more TEMs. One can test both tissues and bodily fluids of a subject. For example, one can test a patient&#39;s blood for evidence of intracellular and membrane associated TEMs, as well as for secreted TEMs. Intracellular and/or membrane associated TEMs may be present in bodily fluids as the result of high levels of expression of these factors and/or through lysis of cells expressing the TEMs.  
         [0042]     Populations of various types of endothelial cells can also be made using the antibodies to endothelial markers of the invention. The antibodies can be used to purify cell populations according to any technique known in the art, including but not limited to fluorescence activated cell sorting. Such techniques permit the isolation of populations which are at least 50, 60, 70, 80, 90, 92, 94, 95, 96, 97, 98, and even 99% the type of endothelial cell desired, whether normal, tumor, or pan-endothelial. Antibodies can be used to both positively select and negatively select such populations. Preferably at least 1, 5, 10, 15, 20, or 25 of the appropriate markers are expressed by the endothelial cell population.  
         [0043]     Populations of endothelial cells made as described herein, can be used for screening drugs to identify those suitable for inhibiting the growth of tumors by virtue of inhibiting the growth of the tumor vasculature.  
         [0044]     Populations of endothelial cells made as described herein, can be used for screening candidate drugs to identify those suitable for modulating angiogenesis, such as for inhibiting the growth of tumors by virtue of inhibiting the growth of endothelial cells, such as inhibiting the growth of the tumor or other undesired vasculature, or alternatively, to promote the growth of endothelial cells and thus stimulate the growth of new or additional large vessel or microvasculature.  
         [0045]     Inhibiting the growth of endothelial cells means either regression of vasculature which is already present, or the slowing or the absence of the development of new vascularization in a treated system as compared with a control system. By stimulating the growth of endothelial cells, one can influence development of new (neovascularization) or additional vasculature development (revascularization). A variety of model screen systems are available in which to test the angiogenic and/or anti-angiogenic properties of a given candidate drug. Typical tests involve assays measuring the endothelial cell response, such as proliferation, migration, differentiation and/or intracellular interaction of a given candidate drug. By such tests, one can study the signals and effects of the test stimuli. Some common screens involve measurement of the inhibition of heparanase, endothelial tube formation on Matrigel, scratch induced motility of endothelial cells, platelet-derived growth factor driven proliferation of vascular smooth muscle cells, and the rat aortic ring assay (which provides an advantage of capillary formation rather than just one cell type).  
         [0046]     Drugs can be screened for the ability to mimic or modulate, inhibit or stimulate, growth of tumor endothelium cells and/or normal endothelial cells. Drugs can be screened for the ability to inhibit tumor endothelium growth but not normal endothelium growth or survival. Similarly, human cell populations, such as normal endothelium populations or tumor endothelial cell populations, can be contacted with test substances and the expression of tumor endothelial markers and/or normal endothelial markers determined. Test substances which decrease the expression of tumor endothelial markers (TEMs) are candidates for inhibiting angiogenesis and the growth of tumors. In cases where the activity of a TEM is known, agents can be screened for their ability to decrease or increase the activity.  
         [0047]     For those tumor endothelial markers identified as being secreted proteins, it is desirable to identify drug candidates capable of binding to the secreted TEM protein. For some applications, the identification of drug candidates capable of interfering with the binding of the secreted TEM to its native receptor is desirable. For other applications, the identification of drug candidates capable of mimicking the activity of the native receptor will be desired. Thus, by manipulating the binding of the secreted TEM:receptor complex, one may be able to promote or inhibit futher development of endothelial cells, and hence, vascularization.  
         [0048]     Expression can be monitored according to any convenient method. Protein or mRNA can be monitored. Any technique known in the art for monitoring specific genes&#39; expression can be used, including but not limited to ELISAs, SAGE, microarray hybridization, Western blots. Changes in expression of a single marker may be used as a criterion for significant effect as a potential pro-angiogenic, anti-angiogenic or anti-tumor agent. However, it also may be desirable to screen for test substances which are able to modulate the expression of at least 5, 10, 15, or 20 of the relevant markers, such as the tumor or normal endothelial markers. Inhibition of TEM protein activity can also be used as a drug screen. Human and mouse TEMS can be used for this purpose.  
         [0049]     Test substances for screening can come from any source. They can be libraries of natural products, combinatorial chemical libraries, biological products made by recombinant libraries, etc. The source of the test substances is not critical to the invention. The present invention provides means for screening compounds and compositions which may previously have been overlooked in other screening schemes. Nucleic acids and the corresponding encoded proteins of the markers of the present invention can be used therapeutically in a variety of modes. TEMs can be used to stimulate the growth of vasculature, such as for wound healing or to circumvent a blocked vessel. The nucleic acids and encoded proteins can be administered by any means known in the art. Such methods include, using liposomes, nanospheres, viral vectors, non-viral vectors comprising polycations, etc. Suitable viral vectors include adenovirus, retroviruses, and sindbis virus. Administration modes can be any known in the art, including parenteral, intravenous, intramuscular, intraperitoneal, topical, intranasal, intrarectal, intrabronchial, etc.  
         [0050]     Specific biological antagonists of TEMs can also be used to therapeutic benefit. For example, antibodies, T cells specific for a TEM, antisense to a TEM, and ribozymes specific for a TEM can be used to restrict, inhibit, reduce, and/or diminish tumor or other abnormal or undesirable vasculature growth. Such antagonists can be administered as is known in the art for these classes of antagonists generally. Anti-angiogenic drugs and agents can be used to inhibit tumor growth, as well as to treat diabetic retinopathy, rheumatoid arthritis, psoriasis, polycystic kidney disease (PKD), and other diseases requiring angiogenesis for their pathologies.  
         [0051]     The above disclosure generally describes the present invention. All references disclosed herein are expressly incorporated by reference. A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only, and are not intended to limit the scope of the invention.  
       EXAMPLE 1  
       [0000]     Visualization of Vasculature of Colorectal Cancers  
         [0052]     The endothelium of human colorectal cancer was chosen to address the issues of tumor angiogenesis, based on the high incidence, relatively slow growth, and resistance to anti-neoplastic agents of these cancers. While certain less common tumor types, such as glioblastomas, are highly vascularized and are regarded as good targets for anti-angiogenic therapy, the importance of angiogenesis for the growth of human colorectal cancers and other common solid tumor types is less well documented.  
         [0053]     We began by staining vessels in colorectal cancers using von Willebrand Factor (vWF) as a marker. In each of 6 colorectal tumors, this examination revealed a high density of vessels throughout the tumor parenchyma (Examples in FIGS. 1 A and B). Interestingly, these analyses also substantiated the importance of these vessels for tumor growth, as endothelium was often surrounded by a perivascular cuff of viable cells, with a ring of necrotic cells evident at the periphery (Example in FIG. 1A). Although these preliminary studies suggested that colon tumors are angiogenesis-dependent, reliable markers that could distinguish vessels in colon cancers from the vessels in normal colon are currently lacking. One way to determine if such markers exist is by analyzing gene expression profiles in endothelium derived from normal and neoplastic tissue.  
       EXAMPLE 2  
       [0000]     Purification of Endothelial Cells  
         [0054]     Global systematic analysis of gene expression in tumor and normal endothelium has been hampered by at least three experimental obstacles. First, endothelium is enmeshed in a complex tissue consisting of vessel wall components, stromal cells, and neoplastic cells, requiring highly selective means of purifying ECs for analysis. Second, techniques for defining global gene expression profiles were not available until recently. And third, only a small fraction of the cells within a tumor are endothelial, mandating the development of methods that are suitable for the analysis of global expression profiles from relatively few cells.  
         [0055]     To overcome the first obstacle, we initially attempted to purify ECs from dispersed human colorectal tissue using CD31, an endothelial marker commonly used for this purpose. This resulted in a substantial enrichment of ECs but also resulted in contamination of the preparations by hematopoietic cells, most likely due to expression of CD31 by macrophages. We therefore developed a new method for purifying ECs from human tissues using P1H12, a recently described marker for ECs. Unlike CD31, P1H12 was specifically expressed on the ECs of both colorectal tumors and normal colorectal mucosa. Moreover, immunofluorescence staining of normal and cancerous colon with a panel of known cell surface endothelial markers (e.g. VE-cadherin, CD31 and CD34) revealed that P1H12 was unique in that it stained all vessels including microvessels (see FIG. 2A and data not shown). In addition to selection with P1H12, it was necessary to optimize the detachment of ECs from their neighbors without destroying their cell surface proteins as well as to employ positive and negative affinity purifications using a cocktail of antibodies (FIG. 2B). The ECs purified from normal colorectal mucosa and colorectal cancers were essentially free of epithelial and hematopoietic cells as judged by RT-PCR (FIG. 2C) and subsequent gene expression analysis (see below).  
       EXAMPLE 3  
       [0000]     Comparison of Tumor and Normal Endothelial Cell Expression Patterns  
         [0056]     To overcome the remaining obstacles, a modification of the Serial Analysis of Gene Expression (SAGE) technique was used. SAGE associates individual mRNA transcripts with 14 base pair tags derived from a specific position near their 3′ termini. The abundance of each tag provides a quantitative measure of the transcript level present within the mRNA population studied. SAGE is not dependent on pre-existing databases of expressed genes, and therefore provides an unbiased view of gene expression profiles. This feature is particularly important in the analysis of cells that constitute only a small fraction of the tissue under study, as transcripts from these cells are unlikely to be well represented in extant EST databases. We adapted the SAGE protocol so that it could be used on small numbers of purified ECs obtained from the procedure outlined in FIG. 2B.  
         [0057]     A library of ˜100,000 tags from the purified ECs of a colorectal cancer, and a similar library from the ECs of normal colonic mucosa from the same patient were generated. These ˜193,000 tags corresponded to over 32,500 unique transcripts. Examination of the expression pattern of hematopoietic, epithelial and endothelial markers confirmed the purity of the preparations (FIG. 2D).  
       EXAMPLE 7  
       [0000]     Tumor Endothelium Markers are Neo-Angiogenic  
         [0058]     Finally, we asked whether these transcripts were expressed in angiogenic states other than that associated with tumorigenesis. We thus performed in situ hybridizations on corpus luteum tissue as well as healing wounds. Although there were exceptions, we found that these transcripts were generally expressed both in the corpus luteum and in the granulation tissue of healing wounds. In all tissues studied, expression of the genes was either absent or exclusively confined to the EC compartment.  
       REFERENCES AND NOTES  
       [0059]     The disclosure of each reference cited is expressly incorporated herein. 
    1. J. Folkman, in  Cancer Medicine  J. Holland, Bast Jr, R C, Morton D L, Frei III, E, Kufe, D W, Weichselbaum, R R, Ed. (Williams &amp; Wilkins, Baltimore, 1997) pp. 181.     2. R. S. Kerbel,  Carcinogenesis  21, 505 (2000).     3. P. Wesseling, D. J. Ruiter, P. C. Burger,  J Neurooncol  32, 253 (1997).     4. Q. G. Dong, et al.,  Arterioscler Thromb Vasc Biol  17, 1599 (1997).     5. P. W. Hewett, J. C. Murray,  In Vitro Cell Dev Biol Anim  32, 462 (1996).     6. M. A. Hull, P. W. Hewett, J. L. Brough, C. J. Hawkey,  Gastroenterology  111, 1230 (1996).     7. G. Haraldsen, et al.,  Gut  37, 225 (1995).     8. The original EC isolation protocol was the same as that shown in FIG. 2B except that dispersed cells were stained with anti-CD31 antibodies instead of anti-P1H12, and magnetic beads against CD64 and CD14 were not included in the negative selection. After generating 120,000 SAGE tags from these two EC preparations, careful analysis of the SAGE data revealed that, in addition to endothelial-specific markers, several macrophage-specific markers were also present.     9. A. Solovey, et al.,  N Engl J Med  337, 1584 (1997).     10. V. E. Velculescu, L. Zhang, B. Vogelstein, K. W. Kinzler,  Science  270, 484-487 (1995).     11. In order to reduce the minimum amount of starting material required from ˜50 million cells to ˜50,000 cells (i.e. ˜1000-fold less) we and others (38) have introduced several modifications to the original SAGE protocol. A detailed version of our modified “MicroSAGE” protocol is available from the authors upon request.     12. 96,694 and 96,588 SAGE tags were analyzed from normal and tumor derived ECs, respectively, and represented 50,298 unique tags. A conservative estimate of 32,703 unique transcripts was derived by considering only those tags observed more than once in the current data set or in the 134,000 transcripts previously identified in human transcriptomes (39).     13. To identify endothelial specific transcripts, we normalized the number of tags analyzed in each group to 100,000, and limited our analysis to transcripts that were expressed at levels at least 20-fold higher in ECs than in non-endothelial cell lines in culture and present at fewer than 5 copies per 100,000 transcripts in non-endothelial cell lines and the hematopoietic fraction (˜57,000 tags)(41). Non-endothelial cell lines consisted of 1.8×106 tags derived from a total of 14 different cancer cell lines including colon, breast, lung, and pancreatic cancers, as well as one non-transformed keratinocyte cell line, two kidney epithelial cell lines, and normal monocytes. A complete list of PEMs is available at www.sagenet.org\angio\table1.htm.     14. M. Tucci, et al.,  J Endocrinol  157, 13 (1998).     15. T. Oono, et al.,  J Invest Dermatol  100, 329 (1993).     16. K Motamed,  Int J Biochem Cell Biol  31, 1363 (1999).     17. N. Bardin, et al.,  Tissue Antigens  48, 531 (1996).     18. D. M. Bradham, A. Igarashi, R. L. Potter, G. R. Grotendorst,  J Cell Biol  114, 1285 (1991).     19. K. Akaogi, et al.,  Proc Natl Acad Sci USA  93, 8384 (1996).     20. Y. Muragali, et al.,  Proc Natl Acad Sci USA  92, 8763 (1995).     21. M. L. Iruela-Arispe, C. A. Diglio, E. H. Sage,  Arterioscler Thromb  11, 805 (1991).     22. J. P. Girard, T. A. Springer,  Immunity  2, 113 (1995).     23. E. A. Jaffe, et al., J Immunol 143, 3961 (1989).     24. J. P. Girard, et al.,  Am J Pathol  155, 2043 (1999).     25. H. Ohtani, N. Sasano,  J Electron Microsc  36, 204 (1987).     26. For non-radioactive in situ hybridization, digoxigenin (DIG)-labelled sense and anti-sense riboprobes were generated through PCR by amplifying 500-600 bp products and incorporating a T7 promoter into the anti-sense primer. In vitro transcription was performed using DIG RNA labelling reagents and T7 RNA polymerase (Roche, Indianapolis, Ind.). Frozen tissue sections were fixed with 4% paraformaldehyde, permeabilized with pepsin, and incubated with 200 ng/ml of riboprobe overnight at 55° C. For signal amplification, a horseradish peroxidase (HRP) rabbit anti-DIG antibody (DAKO, Carpinteria, Calif.) was used to catalyse the deposition of Biotin-Tyramide (from GenPoint kit, DAKO). Further amplification was achieved by adding HRP rabbit anti-biotin (DAKO), biotin-tyramide, and then alkaline-phosphatase (AP) rabbit anti-biotin (DAKO). Signal was detected using the AP substrate Fast Red TR/Napthol AS-MX (Sigma, St. Louis, Mo.), and cells were counterstained with hematoxylin unless otherwise indicated. A detailed protocol including the list of primers used to generate the probes can be obtained from the authors upon request.    
 
         [0086]     27. Transcript copies per cell were calculated assuming an average cell contains 300,000 transcripts. 
    28. R. S. Warren, H. Yuan, M. R. Matli, N. A. Gillett, N. Ferrara,  J Clin Invest  95, 1789 (1995).     29. Y. Takahashi, Y. Kitadai, C. D. Bucana, K. R. Cleary, L. M. Ellis,  Cancer Res  55, 3964 (1995).     30. L. F. Brown, et al.,  Cancer Res  53, 4727 (1993).     31. Endothelial-specific transcripts were defined as those expressed at levels at least 5-fold higher in ECs in vivo than in non-endothelial cell lines in culture (13), and present at no more than 5 copies per 100,000 transcripts in non-endothelial cell lines and the hematopoietic cell fraction (41). Transcripts showing statistically different levels of expression (P&lt;0.05) were then identified using Monte Carlo analysis as previously described (40). Transcripts preferentially expressed in normal endothelium were then defined as those expressed at levels at least 10-fold higher in normal endothelium than in tumor endothelium. Conversely, tumor endothelial transcripts were at least 10-fold higher in tumor versus normal endothelium. See www.sagenet.org\angio\table2.htm and www.sagenet.org\angio\table3.htm for a complete list of differentially expressed genes.     32. M. Iurlaro, et al.,  Eur J Clin Invest  29, 793 (1999).     33. W. S. Lee, et al.,  Circ Res  82, 845 (1998).     34. J. Niquet, A. Represa,  Brain Res Dev Brain Res  95, 227 (1996).     35. L. Fouser, L. Iruela-Arispe, P. Bornstein, E. H. Sage,  J Biol Chem  266, 18345 (1991).     36. M. L. Iruela-Arispe, P. Hasselaar, H. Sage,  Lab Invest  64, 174 (1991).     37. H. F. Dvorak,  N Engl J Med  315, 1650 (1986).     38. B. Virlon, et al.,  Proc Natl Acad Sci USA  96, 15286 (1999).     39. V. E. Velculescu, et al.,  Nat Genet  23, 387 (1999).     40. L. Zhang, et al.,  Science  276, 1268 (1997).     41. Human colon tissues were obtained within ½ hour after surgical removal from patients. Sheets of epithelial cells were peeled away from normal tissues with a glass slide following treatment with 5 mM DDT, then 10 mM EDTA, leaving the lamina propria intact. After a 2 h incubation in collagenase at 37° C., cells were filtered sequentially through 400 um, 100 um, 50 um and 25 um mesh, and spun through a 30% pre-formed Percoll gradient to pellet RBCs. Epithelial cells (Epithelial Fraction), which were found to non-specifically bind magnetic beads, were removed using Dynabeads coupled to BerEP4 (Dynal, Lake Success, N.Y.). Subsequently, macrophages and other leukocytes (Hematopoietic Fraction) were removed using a cocktail of beads coupled to anti-CD45, anti-CD14 and anti-CD64 (Dynal). The remaining cells were stained with P1H12 antibody, purified with anti-mouse IgG-coupled magnetic beads, and lysed in mRNA lysis buffer. A detailed protocol can be obtained from the authors upon request.     42. H. Sheikh, H. Yarwood, A. Ashworth, C. M. Isacke, J Cell Sci 113, 1021-32 (2000).