bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomerase Expression in Noncancerous Bronchial Epithelia Is a Possible Marker of Early Development of Lung Cancer
Authors: Miyazu Yuka Matsuoka , Miyazawa Teruomi , Hiyama Keiko , Kurimoto Noriaki , Iwamoto Yasuo , Matsuura Hiroo , Kanoh Koji , Kohno Nobuoki , Nishiyama Masahiko , Hiyama Eiso 
Published: November 2005

AbstractCentrally located lung cancers in smokers frequently associated with subsequent primary tumors. We evaluated the telomerase expression chronologically in noncancerous epithelia as a risk factor of susceptibility to lung cancer development. Telomerase protein expression was examined in situ by immunohistochemistry in 26 noncancerous bronchial epithelia adjacent to centrally located early-stage lung cancers in sequential 23 patients treated by photodynamic therapy or surgery among 206 patients who underwent autofluorescence bronchoscopy from 1997 to 2003. Among the 15 lesions in 12 patients treated by photodynamic therapy alone, 11 lesions achieved complete remission after photodynamic therapy, and none of their noncancerous bronchial epithelia was telomerase positive. On the contrary, in the remaining four lesions, either recurrence or secondary lung cancer developed adjacent to the successfully treated primary cancer within 26 months, and the telomerase protein expression in noncancerous epithelia was detected before the secondary cancer development (P &lt; 0.001). The overall relationship of human telomerase reverse transcriptase positivity in noncancerous epithelia and subsequent lung cancer development, including patients treated by radiation or surgery, showed higher significance (P &lt; 0.0001). Histologically “normal” bronchial epithelia in smokers may unphysiologically express telomerase as a field, and such epithelia are likely susceptible to develop lung cancer. We propose that ectopic expression of telomerase in bronchial epithelia may precede transformation in human lung cancer development and that detection of telomerase protein in noncancerous bronchial epithelia will become a useful marker detecting high-risk patients for lung cancer development.
Mitochondrially Targeted p53 Has Tumor Suppressor Activities In vivo
Authors: Talos Flaminia , Petrenko Oleksi , Mena Patricio , Moll Ute M. 
Published: November 2005

Abstract
Complex proapoptotic functions are essential for the tumor suppressor activity of p53. We recently described a novel transcription-independent mechanism that involves a rapid proapoptotic action of p53 at the mitochondria and executes the shortest known circuitry of p53 death signaling. Here, we examine if this p53-dependent mitochondrial program could be exploited for tumor suppression in vivo. To test this, we engage Eμ-Myc transgenic mice, a well-established model of p53-dependent lymphomagenesis. We show that exclusive delivery of p53 to the outer mitochondrial membrane confers a significant growth disadvantage on Eμ-Myc–transformed B-cells of p53-deficient or alternate reading frame–deficient genotypes, resulting in efficient induction of apoptosis and impinged proliferation. Conversely, normal cells from thymus, spleen, and bone marrow showed poor infectivity with these viruses. This proof-of-principle experiment shows that exclusive reliance on the direct mitochondrial program exerts a significant tumor suppressor activity in vivo. Our in vivo data on the direct mitochondrial apoptotic p53 program lays the groundwork to further investigate its efficacy and safety and to address its possible therapeutic value in the future.
Up-regulation of CXCR4 Expression in PC-3 Cells by Stromal-Derived Factor-1α (CXCL12) Increases Endothelial Adhesion and Transendothelial Migration: Role of MEK/ERK Signaling Pathway–Dependent NF-κB Activation
Authors: Kukreja Promil , Abdel-Mageed Asim B. , Mondal Debasis , Liu Kai , Agrawal Krishna C. 
Published: November 2005

AbstractThe chemokine stromal-derived factor-1α (SDF-1α/CXCL-12) and its receptor, CXCR4, play a crucial role in adhesion and transendothelium migration (TEM) of prostate cancer cells. We tested the hypothesis that enhanced expression of CXCR4 in prostate cancer cells is dependent upon SDF-1α-mediated activation of nuclear factor-κB (NF-κB). SDF-1α increased the CXCR4 mRNA and protein expression in PC-3 cells but not in LNCaP cells. Similarly, SDF-1α enhanced the NF-κB-dependent transcriptional activity in PC-3 cells but not in LNCaP cells. SDF-1α increased PC-3 cell adhesion to the human umbilical vein endothelial cell monolayer and enhanced TEM, which was abrogated with anti-CXCR4 monoclonal antibody (mAb). Suppression of NF-κB activity in PC-3 cells by a mutant IκBα super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited adhesion and TEM. Transient overexpression of p65 subunit of NF-κB in PC-3 cells up-regulated CXCR4 receptor expression and increased the adhesion and TEM of these cells in response to SDF-1α gradient. Treatment of PC-3 cells with SDF-1α leads to nuclear translocation of NF-κB protein within 15 to 30 minutes, which correlated with IκBα phosphorylation. A p42/44 mitogen-activated protein kinase [MAPK, extracellular signal regulated kinase-1/2 (ERK-1/2)] biphasic activation pattern was observed in these cells at 15 minutes and 3 hours after SDF-1α treatment. Phosphorylation of IκB kinase α was observed within 30 minutes, which was blocked by PD98059 [MAPK kinase (MEK) inhibitor]. PD98059 cotreatment significantly inhibited SDF-1α-induced NF-κB reporter activity and CXCR4 receptor expression as shown by flow cytometry. These data suggest that SDF-1α-induced expression of CXCR4 in PC-3 cells is dependent on MEK/ERK signaling cascade and NF-κB activation.
Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma
Authors: Batchu Ramesh B. , Moreno Amberly M. , Szmania Susann M. , Bennett Grant , Spagnoli Guilio C. , Ponnazhagan Selvarangan , Barlogie Bart , Tricot Guido , van Rhee Frits 
Published: November 2005

AbstractMyeloma vaccines, based on dendritic cells pulsed with idiotype or tumor lysate, have been met with limited success, probably in part due to insufficient cross-priming of myeloma antigens. A powerful method to introduce myeloma-associated antigens into the cytosol of dendritic cells is protein transduction, a process by which proteins fused with a protein transduction domain (PTD) freely traverse membrane barriers. NY-ESO-1, an immunogenic antigen by itself highly expressed in 60% of high-risk myeloma patients, was purified to near homogeneity both alone and as a recombinant fusion protein with a PTD, derived from HIV-Tat. Efficient entry of PTD-NY-ESO-1 into dendritic cells, confirmed by microscopy, Western blotting, and intracellular flow cytometry, was achieved without affecting dendritic cell phenotype. Experiments with amiloride, which inhibits endocytosis, and N-acetyl-l-leucinyl-l-norleucinal, a proteasome inhibitor, confirmed that PTD-NY-ESO-1 entered dendritic cells by protein transduction and was degraded by the proteasome. Tetramer analysis indicated superior generation of HLA-A2.1, CD8+ T lymphocytes specific for NY-ESO-1157-165 with PTD-NY-ESO-1 compared with NY-ESO-1 control protein (44% versus 2%, respectively). NY-ESO-1-specific T lymphocytes generated with PTD-NY-ESO-1 secreted IFN-γ indicative of a Tc1-type cytokine response. Thus, PTD-NY-ESO-1 accesses the cytoplasm by protein transduction, is processed by the proteasome, and NY-ESO-1 peptides presented by HLA class I elicit NY-ESO-1-specific T lymphocytes.
Focal Adhesion Kinase Regulates Syndecan-2–Mediated Tumorigenic Activity of HT1080 Fibrosarcoma Cells
Authors: Park Haein , Han Innoc , Kwon Ho Jeong , Oh Eok-Soo 
Published: November 2005

Abstract
Expression of syndecan-2, a transmembrane heparan sulfate proteoglycan, is crucial for the tumorigenic activity in colon carcinoma cells. However, despite the high-level expression of syndecan-2 in mesenchymal cells, few studies have addressed the function of syndecan-2 in sarcoma cells. In HT1080 fibrosarcoma cells, we found that syndecan-2 regulated migration, invasion into Matrigel, and anchorage-independent growth but not cell-extracellular matrix adhesion or proliferation, suggesting that syndecan-2 plays different functional roles in fibrosarcoma and colon carcinoma cells. Consistent with the increased cell migration/invasion of syndecan-2–overexpressing HT1080 cells, syndecan-2 overexpression increased phosphorylation and interaction of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K), membrane localization of T-lymphoma invasion and metastasis gene-1 (Tiam-1), and activation of Rac. Syndecan-2–mediated cell migration/invasion of HT1080 cells was diminished when (a) cells were cotransfected with nonphosphorylatable mutant FAK Y397F or with other FAK mutants lacking PI3K interactions, (b) cells were treated with a specific PI3K inhibitor, or (c) levels of Tiam-1 were knocked down with small interfering RNAs. Furthermore, expression of several FAK mutants inhibited syndecan-2–mediated enhancement of anchorage-independent growth in HT1080 cells. Taken together, these data suggest that syndecan-2 regulates the tumorigenic activities of HT1080 fibrosarcoma cells and that FAK is a key regulator of syndecan-2–mediated tumorigenic activities.
Novel Pheochromocytoma Susceptibility Loci Identified by Integrative Genomics
Authors: Dahia Patricia L.M. , Hao Ke , Rogus John , Colin Christian , Pujana Miguel A.G. , Ross Ken , Magoffin Danielle , Aronin Neil , Cascon Alberto , Hayashida César Y. , Li Cheng , Toledo Sérgio P.A. , Stiles Charles D. ,   for the Familial Pheochromocytoma Consortium
Published: November 2005

Abstract
Pheochromocytomas are catecholamine-secreting tumors that result from mutations of at least six different genes as components of distinct autosomal dominant disorders. However, there remain familial occurrences of pheochromocytoma without a known genetic defect. We describe here a familial pheochromocytoma syndrome consistent with digenic inheritance identified through a combination of global genomics strategies. Multipoint parametric linkage analysis revealed identical LOD scores of 2.97 for chromosome 2cen and 16p13 loci. A two-locus parametric linkage analysis produced maximum LOD score of 5.16 under a double recessive multiplicative model, suggesting that both loci are required to develop the disease. Allele-specific loss of heterozygosity (LOH) was detected only at the chromosome 2 locus in all tumors from this family, consistent with a tumor suppressor gene. Four additional pheochromocytomas with a similar genetic pattern were identified through transcription profiling and helped refine the chromosome 2 locus. High-density LOH mapping with single nucleotide polymorphism–based array identified a total of 18 of 62 pheochromocytomas with LOH within the chromosome 2 region, which further narrowed down the locus to &lt;2 cM. This finding provides evidence for two novel susceptibility loci for pheochromocytoma and adds a recessive digenic trait to the increasingly broad genetic heterogeneity of these tumors. Similarly, complex traits may also be involved in other familial cancer syndromes.
Addressing the “Fas Counterattack” Controversy: Blocking Fas Ligand Expression Suppresses Tumor Immune Evasion of Colon CancerIn vivo
Authors: Ryan Aideen E. , Shanahan Fergus , O'Connell Joe , Houston Aileen M. 
Published: November 2005

AbstractFas ligand (FasL/CD95L) is a transmembrane protein belonging to the tumor necrosis factor superfamily that can trigger apoptotic cell death following ligation to its receptor, Fas (CD95/APO-1). Expression of FasL may help to maintain tumor cells in a state of immune privilege by inducing apoptosis of antitumor immune effector cells—the “Fas counterattack.” However, the ability of FasL to mediate tumor immune privilege is controversial due to studies that indicate FasL has both pro- and anti-inflammatory activities. To resolve this controversy and functionally define the role of FasL in tumor immune evasion, we investigated if suppression of endogenously expressed FasL in colon tumor cells resulted in reduced tumor development and improved antitumor immune challenge in vivo. Specifically, FasL expression in CMT93 colon carcinoma cells was down-regulated following stable transfection with a plasmid encoding antisense FasL cDNA. Down-regulation of FasL expression had no effect on tumor growth in vitro but significantly reduced tumor development in syngeneic immunocompetent mice in vivo. Tumor size was also significantly decreased. Reduced FasL expression by tumor cells led to increased lymphocyte infiltration. The overall level of neutrophils present in all of the tumors examined was low, with no difference between the tumors, irrespective of FasL expression. Thus, down-regulation of FasL expression by colon tumor cells results in an improved antitumor immune challenge in vivo, providing functional evidence in favor of the “Fas counterattack” as a mechanism of tumor immune evasion.
The Role of DOC-2/DAB2 in Modulating Androgen Receptor–Mediated Cell Growth via the Nongenomic c-Src–Mediated Pathway in Normal Prostatic Epithelium and Cancer
Authors: Zhoul Jian , Hernandez Gina , Tu Szu-Wei , Huang Chien-Ling , Tseng Ching-Ping , Hsieh Jer-Tsong 
Published: November 2005

Abstract
Prostate cancer is initially responsive to androgen ablation, but prostate cancer tumors invariably progress to an androgen-independent state that is ultimately lethal. The onset of the androgen-independent prostate cancer is often associated with up-regulation of the androgen receptor that can cause antagonists to exhibit agonistic activity, which could lead to the failure of androgen ablation therapy. We describe a unique protein—DOC-2/DAB2 (differentially expressed in ovarian cancer-2/disabled 2)—that antagonizes androgen receptor–mediated cell growth in prostate cancer cells via interaction with c-Src protein. This interaction causes inactivation of Erk and Akt proteins critical for proliferation and survival of prostate cancer cells. However, DOC-2/DAB2 does not change the capacity of androgen receptor to regulate the transcription of androgen-responsive reporter genes, indicating that DOC-2/DAB2 selectively inhibits androgen receptor–mediated cell growth in androgen-independent prostate cancer by disrupting the androgen receptor/c-Src complex. In normal prostatic epithelia, DOC-2/DAB2 protein levels are more abundant than androgen receptor protein levels and reduced endogenous DOC-2/DAB2 protein levels in these cells by DOC-2/DAB2 RNA interference result in enhancing androgen receptor–mediated cell growth. We conclude that DOC-2/DAB2 can modulate androgen receptor–mediated cell growth in both normal and malignant prostatic epithelial cells and the outcome of this study could evolve into a new therapeutic strategy of prostate cancer.
Fine Mapping Reveals Multiple Loci and a Possible Epistatic Interaction within the Mammary Carcinoma Susceptibility Quantitative Trait Locus, Mcs5
Authors: Samuelson David J. , Aperavich Beth A. , Haag Jill D. , Gould Michael N. 
Published: November 2005

Abstract
To identify high-frequency, low-penetrance breast cancer modifier genes, we have developed a rat genetic model that uses the Wistar-Kyoto (WKy) inbred strain, resistant to developing 7,12-dimethylbenz[a]anthracene–induced mammary carcinogenesis, as a congenic donor and the susceptible Wistar-Furth (WF) strain as the recipient. Here, data from congenic rat lines containing smaller WKy genomic intervals of the Mcs5 quantitative trait locus region are presented to fine map three independently acting Mcs5 subloci. WKy-homozygous females from congenic lines defining Mcs5a, Mcs5b, and Mcs5c averaged, respectively, 4.0 ± 0.4, 11.6 ± 0.6, and 3.5 ± 0.4 mammary carcinomas per rat. These phenotypic values are statistically different from the WF-homozygous phenotype value of 8.0 ± 0.4, which is the baseline phenotype used for these experiments. We identified a likely Mcs5a × Mcs5b epistatic interaction that results in masking the increased susceptibility effect of the Mcs5b WKy allele by the Mcs5a WKy allele. We also provide evidence for a Mcs5a × Mcs5c interaction that is synergistic to decrease mammary carcinoma susceptibility below the additive effects of WKy alleles at each locus independently. The Mcs5 subloci are currently localized to 1.0, 7.5, and 4.5 Mb of rat chromosome 5, and the orthologous regions are on human chromosome 9 and mouse chromosome 4. These loci will provide unbiased candidate gene loci for evaluation in human case-control association studies.
A Network of Genetic Events Sufficient to Convert Normal Human Cells to a Tumorigenic State
Authors: Kendall S. DiSean , Linardic Corinne M. , Adam Stacey J. , Counter Christopher M. 
Published: November 2005

Abstract
Although great progress has been made at identifying and characterizing individual genes involved in cancer, less is known about how the combination of such genes collaborate to form tumors in humans. To this end, we sought to genetically recreate tumorigenesis in normal human cells using genes altered in human cancer. We now show that expression of mammalian proteins that inactivate the tumor suppressors Rb and p53 in conjunction with the oncoproteins Ras and Myc and the telomerase subunit hTERT is sufficient to drive a number of normal human somatic cells to a tumorigenic fate. This provides a blueprint of the events that lead to human cancer, allowing different cancers to be genetically modeled from normal human cells.
High Correlation of Whole-Body Red Fluorescent Protein Imaging and Magnetic Resonance Imaging on an Orthotopic Model of Pancreatic Cancer
Authors: Bouvet Michael , Spernyak Joseph , Katz Matthew H. , Mazurchuk Richard V. , Takimoto Shinako , Bernacki Ralph , Rustum Youcef M. , Moossa Abdool R. , Hoffman Robert M. 
Published: November 2005

Abstract
We have developed genetically fluorescent orthotopic models of human pancreatic cancer. In these models, noninvasive fluorescent protein imaging (FPI) of internal primary tumors and metastatic deposits has been carried out. Whole-body tumor images are easily and inexpensively obtained using FPI, permitting both detection and quantification of tumor load. In this study, we simultaneously compared single mice with a highly fluorescent, red fluorescent protein–expressing orthotopic pancreatic cancer xenografts with both FPI and high-resolution magnetic resonance imaging (MRI). Images were acquired at multiple time points after tumor implantation in the pancreas. Indwelling pancreatic primary tumors and metastatic foci were detected by both FPI and MRI. Moreover, a strong correlation existed between images taken with these two technologies. FPI permitted rapid, high-throughput imaging without the need for either anesthesia or contrast agents. Both FPI and MRI enabled accurate imaging of tumor growth and metastasis, although MRI enabled tissue structure to be visualized as well. FPI has high resolution and is exceedingly rapid with instant image capture. We suggest a complimentary role for these two imaging modalities.
Induction of Hepatocyte Growth Factor/Scatter Factor by Fibroblast Clustering Directly Promotes Tumor Cell Invasiveness
Authors: Kankuri Esko , Cholujova Dana , Comajova Monika , Vaheri Antti , Bizik Jozef 
Published: November 2005

Abstract
For determining the malignant behavior of a tumor, paracrine interactions between stromal and cancer cells are crucial. We previously reported that fibroblast clustering induces cyclooxygenase-2 (COX-2), plasminogen activation, and programmed necrosis, all of which were significantly reduced by nonsteroidal anti-inflammatory drugs (NSAID). We have now found that tumor cell–conditioned medium induces similar fibroblast clustering. Activation of the necrotic pathway in clustering fibroblasts, compared with control monolayer cultures, induced a massive &gt;200-fold production of bioactive hepatocyte growth factor/scatter factor (HGF/SF), which made human carcinoma cells spread and invade a collagen lattice. This response occurred only if a functional, properly processed c-Met receptor was present, which was then rapidly phosphorylated. The invasion-promoting activity was inhibited by a neutralizing HGF/SF antibody. NSAIDs, if added early during fibroblast aggregation, inhibited HGF/SF production effectively but had no effect at later stages of cell aggregation. Our results thus provide the first evidence that aggravated progression of tumors with necrotic foci may involve paracrine reciprocal signaling leading to stromal activation by direct cell-cell contact (i.e., nemosis).
HIN-1, an Inhibitor of Cell Growth, Invasion, and AKT Activation
Authors: Krop Ian , Parker Michele Taylor , Bloushtain-Qimron Noga , Porter Dale , Gelman Rebecca , Sasaki Hidefumi , Maurer Matthew , Terry Mary Beth , Parsons Ramon , Polyak Kornelia 
Published: November 2005

Abstract
The HIN-1 gene encoding a small, secreted protein is silenced due to methylation in a substantial fraction of breast, prostate, lung, and pancreatic carcinomas, suggesting a potential tumor suppressor function. The receptor of HIN-1 is unknown, but ligand-binding studies indicate the presence of high-affinity cell surface HIN-1 binding on epithelial cells. Here, we report that HIN-1 is a potent inhibitor of anchorage-dependent and anchorage-independent cell growth, cell migration, and invasion. Expression of HIN-1 in synchronized cells inhibits cell cycle reentry and the phosphorylation of the retinoblastoma protein (Rb), whereas in exponentially growing cells, HIN-1 induces apoptosis without apparent cell cycle arrest and effect on Rb phosphorylation. Investigation of multiple signaling pathways revealed that mitogen-induced phosphorylation and activation of AKT are inhibited in HIN-1–expressing cells. In addition, expression of constitutively activate AKT abrogates HIN-1–mediated growth arrest. Taken together, these studies provide further evidence that HIN-1 possesses tumor suppressor functions, and that these activities may be mediated through the AKT signaling pathway.
An In vivo Tumor Model Exploiting Metabolic Response as a Biomarker for Targeted Drug Development
Authors: Cullinane Carleen , Dorow Donna S. , Kansara Maya , Conus Nelly , Binns David , Hicks Rodney J. , Ashman Leonie K. , McArthur Grant A. , Thomas David M. 
Published: November 2005

Abstract
In vivo models that recapitulate oncogene-dependent tumorigenesis will greatly facilitate development of molecularly targeted anticancer therapies. We have developed a model based on activating mutations in c-KIT in gastrointestinal stromal tumors (GISTs). This model comprises murine tumors of FDC-P1 cell lines expressing c-KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to the small-molecule c-KIT inhibitor, imatinib. Clinically, GIST response to imatinib is associated with rapid reduction in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), preceding changes in conventional response criteria by several weeks. Using the FDC-P1 model in small animal PET, FDG uptake into tumors expressing the c-KIT V560G mutation was significantly reduced as early as 4 hours after imatinib treatment. In contrast, no change in FDG uptake was observed in resistant c-KIT D816V-expressing tumors after 48 hours of imatinib treatment. Consistent with the PET results, expression of the glucose transporter, GLUT1, was significantly reduced in V560G tumors at 4 hours, preceding changes in markers of proliferation by several hours. In vitro, imatinib treatment of V560G cells resulted in a reduction of glucose transporter numbers at the cell surface and decreased glucose uptake well before changes in cell viability. Notably, decreased ambient glucose concentrations enhanced the cytotoxic effect of imatinib. Taken together, these data account for the rapidity and significance of the PET response to imatinib and suggest that metabolic effects may contribute to imatinib cytotoxicity. Further, the FDC-P1 model represents a very useful paradigm for molecularly targeted drug development.