bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host-Derived Angiopoietin-2 Affects Early Stages of Tumor Development and Vessel Maturation but Is Dispensable for Later Stages of Tumor Growth
Authors: Nasarre Patrick , Thomas Markus , Kruse Karoline , Helfrich Iris , Wolter Vivien , Deppermann Carleen , Schadendorf Dirk , Thurston Gavin , Fiedler Ulrike , Augustin Hellmut G. 
Published: February 2009

Abstract
The angiopoietin/Tie2 system has been identified as the second vascular-specific receptor tyrosine kinase system controlling vessel assembly, maturation, and quiescence. Angiopoietin-2 (Ang-2) is prominently up-regulated in the host-derived vasculature of most tumors, making it an attractive candidate for antiangiogenic intervention. Yet, the net outcome of Ang-2 functions on tumor angiogenesis is believed to be contextual depending on the local cytokine milieu. Correspondingly, Ang-2 manipulatory therapies have been shown to exert protumorigenic as well as antitumorigenic effects. To clarify the role of Ang-2 for angiogenesis and tumor growth in a definite genetic experimental setting, the present study was aimed at comparatively studying the growth of different tumors in wild-type and Ang-2–deficient mice. Lewis lung carcinomas, MT-ret melanomas, and B16F10 melanomas all grew slower in Ang-2–deficient mice. Yet, tumor growth in wild-type and Ang-2–deficient mice dissociated during early stages of tumor development, whereas tumor growth rates during later stages of primary tumor progression were similar. Analysis of the intratumoral vascular architecture revealed no major differences in microvessel density and perfusion characteristics. However, diameters of intratumoral microvessels were smaller in tumors grown in Ang-2–deficient mice, and the vasculature had an altered pattern of pericyte recruitment and maturation. Ang-2–deficient tumor vessels had higher pericyte coverage indices. Recruited pericytes were desmin and NG2 positive and predominately α-smooth muscle actin negative, indicative of a more mature pericyte phenotype. Collectively, the experiments define the role of Ang-2 during tumor angiogenesis and establish a better rationale for combination therapies involving Ang-2 manipulatory therapies. [Cancer Res 2009;69(4):1324–33]
Specific Cross-talk between Epidermal Growth Factor Receptor and Integrin αvβ5 Promotes Carcinoma Cell Invasion and Metastasis
Authors: Ricono Jill M. , Huang Miller , Barnes Leo A. , Lau Steven K. , Weis Sara M. , Schlaepfer David D. , Hanks Steven K. , Cheresh David A. 
Published: February 2009

AbstractTyrosine kinase receptors and integrins play essential roles in tumor cell invasion and metastasis. Previously, we showed that epidermal growth factor (EGF) stimulation of pancreatic carcinoma cells led to invasion and metastasis that was blocked by antagonists of integrin αvβ5. Here, we show that EGF stimulates metastasis of carcinoma cells via a Src-dependent phosphorylation of p130 CAS leading to activation of Rap1, a small GTPase involved in integrin activation. Specifically, EGF receptor (EGFR)–induced Src activity leads to phosphorylation of a region within the CAS substrate domain, which is essential for Rap1 and αvβ5 activation. This pathway induces αvβ5-mediated invasion and metastasis in vivo yet does not influence primary tumor growth or activation of other integrins on these cells. These findings show cross-talk between a tyrosine kinase receptor and an integrin involved in carcinoma cell invasion and metastasis and may explain in part how inhibitors of EGFR affect malignant disease. [Cancer Res 2009;69(4):1383–91]
Depletion of Cytosolic Phospholipase A2 in Bone Marrow–Derived Macrophages Protects against Lung Cancer Progression and Metastasis
Authors: Weiser-Evans Mary C.M. , Wang Xue-Qing , Amin Jay , Van Putten Vicki , Choudhary Rashmi , Winn Robert A. , Scheinman Robert , Simpson Peter , Geraci Mark W. , Nemenoff Raphael A. 
Published: February 2009

AbstractCancer progression and metastasis involves interactions between tumor cells and the tumor microenvironment (TME). We reported that mice deficient for cytosolic phospholipase A2 (cPLA2-KO) are protected against the development of lung tumors. The goal of this study was to examine the role of cPLA2 in the TME. Mouse lung cancer cells (CMT167 and Lewis lung carcinoma cells) injected directly into lungs of syngeneic mice formed a primary tumor, and then metastasized to other lobes of the lung and to the mediastinal lymph nodes. Identical cells injected into cPLA2-KO mice showed a dramatic decrease in the numbers of secondary metastatic tumors. This was associated with decreased macrophage staining surrounding the tumor. Wild-type mice transplanted with cPLA2-KO bone marrow had a marked survival advantage after inoculation with tumor cells compared with mice receiving wild-type (WT) bone marrow. In vitro, coculturing CMT167 cells with bone marrow–derived macrophages from WT mice increased production of interleukin 6 (IL-6) by cancer cells. This increase was blocked in cocultures using cPLA2-KO macrophages. Correspondingly, IL-6 staining was decreased in tumors grown in cPLA2-KO mice. These data suggest that stromal cPLA2 plays a critical role in tumor progression by altering tumor-macrophage interactions and cytokine production. [Cancer Res 2009;69(5):1733–8]
Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion
Authors: Wrage Michaela , Ruosaari Salla , Eijk Paul P. , Kaifi Jussuf T. , Hollmén Jaakko , Yekebas Emre F. , Izbicki Jakob R. , Brakenhoff Ruud H. , Streichert Thomas , Riethdorf Sabine , Glatzel Markus , Ylstra Bauke , Pantel Klaus , Wikman Harriet 
Published: February 2009

Abstract
Purpose: Bone marrow is a common homing organ for early disseminated tumor cells (DTC) and their presence can predict the subsequent occurrence of overt metastasis and survival in lung cancer. It is still unclear whether the shedding of DTC from the primary tumor is a random process or a selective release driven by a specific genomic pattern.
Experimental Design: DTCs were identified in bone marrow from lung cancer patients by an immunocytochemical cytokeratin assay. Genomic aberrations and expression profiles of the respective primary tumors were assessed by microarrays and fluorescence in situ hybridization analyses. The most significant results were validated on an independent set of primary lung tumors and brain metastases.
Results: Combination of DNA copy number profiles (array comparative genomic hybridization) with gene expression profiles identified five chromosomal regions differentiating bone marrow-negative from bone marrow-positive patients (4q12-q32, 10p12-p11, 10q21-q22, 17q21, and 20q11-q13). Copy number changes of 4q12-q32 were the most prominent finding, containing the highest number of differentially expressed genes irrespective of chromosomal size (P = 0.018). Fluorescence in situ hybridization analyses on further primary lung tumor samples confirmed the association between loss of 4q and bone marrow-positive status. In bone marrow-positive patients, 4q was frequently lost (37% versus 7%), whereas gains could be commonly found among bone marrow-negative patients (7% versus 17%). The same loss was also found to be common in brain metastases from both small and non-small cell lung cancer patients (39%).
Conclusions: Thus, our data indicate, for the first time, that early hematogenous dissemination of tumor cells might be driven by a specific pattern of genomic changes.
Targeting Akt3 Signaling in Malignant Melanoma Using Isoselenocyanates
Authors: Sharma Arati , Sharma Arun K. , Madhunapantula SubbaRao V. , Desai Dhimant , Huh Sung Jin , Mosca Paul , Amin Shantu , Robertson Gavin P. 
Published: February 2009

Abstract
Purpose: Melanoma is the most invasive and deadly form of skin cancer. Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas because its activity is increased in ∼70% of tumors, decreasing apoptosis in order to promote tumorigenesis.
Experimental Design: Because naturally occurring products can be effective anticancer agents, a library was screened to identify Akt3 pathway inhibitors. Isothiocyanates were identified as candidates, but low potency requiring high concentrations for therapeutic efficacy made them unsuitable. Therefore, more potent analogs called isoselenocyanates were created using the isothiocyanate backbone but increasing the alkyl chain length and replacing sulfur with selenium. Efficacy was measured on cultured cells and tumors by quantifying proliferation, apoptosis, toxicity, and Akt3 pathway inhibition.
Results: Isoselenocyanates significantly decreased Akt3 signaling in cultured melanoma cells and tumors. Compounds having 4 to 6 carbon alkyl side chains with selenium substituted for sulfur, called ISC-4 and ISC-6, respectively, decreased tumor development by ∼60% compared with the corresponding isothiocyanates, which had no effect. No changes in animal body weight or in blood parameters indicative of liver-, kidney-, or cardiac-related toxicity were observed with isoselenocyanates. Mechanistically, isoselenocyanates ISC-4 and ISC-6 decreased melanoma tumorigenesis by causing an ∼3-fold increase in apoptosis.
Conclusions: Synthetic isoselenocyanates are therapeutically effective for inhibiting melanoma tumor development by targeting Akt3 signaling to increase apoptosis in melanoma cells with negligible associated systemic toxicity.
A Systems Perspective of Ras Signaling in Cancer
Authors: Stites Edward C. , Ravichandran Kodi S. 
Published: February 2009

Abstract
The development of cancer reflects the complex interactions and properties of many proteins functioning as part of large biochemical networks within the cancer cell. Although traditional experimental models have provided us with wonderful insights on the behavior of individual proteins within a cancer cell, they have been deficient in simultaneously keeping track of many proteins and their interactions in large networks. Computational models have emerged as a powerful tool for investigating biochemical networks due to their ability to meaningfully assimilate numerous network properties. Using the well-studied Ras oncogene as an example, we discuss the use of models to investigate pathologic Ras signaling and describe how these models could play a role in the development of new cancer drugs and the design of individualized treatment regimens.
Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma
Authors: Lam Wing , Bussom Scott , Cheng Yung-Chi 
Published: February 2009

Abstract
β-l-Dioxolane-cytidine (l-OddC; BCH-4556; troxacitabine), a novel l-configuration deoxycytidine analogue, was under clinical trials for treating cancer. The cytotoxicity of l-OddC is dependent on its phosphorylation to l-OddCTP by phosphoglycerate kinase (PGK) and its subsequent addition into nuclear DNA. Because PGK is induced with hypoxia, the expression of hypoxia-inducible factor-1α and PGK of H460 cells (human non-small cell lung carcinoma) in vitro and in vivo was studied. In culture, hypoxic treatment induced the protein expression of PGK by 3-fold but had no effect on the protein expression of other l-OddC metabolism-associated enzymes such as apurinic/apyrimidinic endonuclease-1, deoxycytidine kinase, CMP kinase, and nM23 H1. Using a clonogenic assay, hypoxic treatment of H460 cells rendered cells 4-fold more susceptible to l-OddC but not to gemcitabine (dFdC) following exposure to drugs for one generation. Using hypoxia response element-luciferase reporter system, Western blotting, and immunohistochemistry, it was found that hypoxia-inducible factor-1α and PGK expression increased and could be correlated to tumor size. Despite dFdC being more toxic than l-OddC in cell culture, l-OddC (300 mg/kg i.p.) had a stronger antitumor activity than dFdC in H460 xenograft-bearing nude mice. Furthermore, l-OddC retained ∼50% of its antitumor activity with oral gavage compared with i.p. delivery. Oral administration of l-OddC (600 mg/kg p.o.) had a similar area under the curve value compared with i.p. injection of dFdC (300 mg/kg i.p.). In conclusion, the hypoxia, which commonly exists in non-small cell lung carcinoma or other solid tumors resistant to radiotherapy or chemotherapy, is a favorable determinant to enhance the antitumor activity of l-OddC in vivo. [Mol Cancer Ther 2009;8(2):415–23]
EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma
Authors: Seeliger Hendrik , Camaj Peter , Ischenko Ivan , Kleespies Axel , De Toni Enrico N. , Thieme Susanne E. , Blum Helmut , Assmann Gerald , Jauch Karl-Walter , Bruns Christiane J. 
Published: February 2009

Abstract
The progression of pancreatic cancer is dependent on local tumor growth, angiogenesis, and metastasis. EFEMP1, a recently discovered member of the fibulin family, was characterized with regard to these key elements of pancreatic cancer progression.
Differential gene expression was assessed by mRNA microarray hybridization in FG human pancreatic adenocarcinoma cells and L3.6pl cells, a highly metastatic variant of FG. In vivo orthotopic tumor growth of EFEMP1-transfected FG cells was examined in nude mice. To assess the angiogenic properties of EFEMP1, vascular endothelial growth factor (VEGF) production of tumor cells, endothelial cell proliferation and migration, and tumor microvessel density were analyzed in response to EFEMP1. Further, tumor cell apoptosis, cell cycle progression, and resistance to cytotoxic agents were quantitated by propidium iodide staining and flow cytometry. In microarray hybridization, EFEMP1 was shown to be significantly up-regulated in L3.6pl cells compared with FG cells. Concordantly, EFEMP1 transfection of FG cells stimulated orthotopic and metastatic tumor growth in vivo. EFEMP1 expression resulted in a stimulation of VEGF production by tumor cells and an increased number of CD31-positive microvessels. Endothelial cell proliferation and migration were not altered by EFEMP1, indicating an indirect angiogenic effect. Further, EFEMP1 expression decreased apoptosis and promoted cell cycle progression in response to serum starvation or exposure to gemcitabine, 5-fluorouracil, and irinotecan.
EFEMP1 has protumorigenic effects on pancreatic cancer in vivo and in vitro mediated by VEGF-driven angiogenesis and antiapoptotic mechanisms. Hence, EFEMP1 is a promising candidate for assessing prognosis and individualizing therapy in a clinical tumor setting. (Mol Cancer Res 2009;7(2):189–98)
Annexin-1 Regulates Growth Arrest Induced by High Levels of Estrogen in MCF-7 Breast Cancer Cells
Authors: Ang Emily Zhao-Feng , Nguyen Hung Thanh , Sim Hui-Ling , Putti Thomas C. , Lim Lina H.K. 
Published: February 2009

Abstract
Estrogen, a naturally occurring female steroid growth hormone, has been implicated as a major risk factor for the development of breast cancer. Recent research into this disease has also correlated Annexin-1 (ANXA1), a glucocorticoid-inducible protein, with the development of breast tumorigenesis. ANXA1 is lost in many cancers, including breast cancer, and this may result in a functional promotion of tumor growth. In this study, we investigated the expression of ANXA1 in MCF-7 cells treated with estrogen and the regulation of estrogen functions by ANXA1. Exposure of MCF-7 breast cancer cells to high physiologic levels (up to 100 nmol/L) of estrogen leads to an up-regulation of ANXA1 expression partially through the activation of cyclic AMP-responsive element binding protein and dependency on activation of the estrogen receptor. In addition, treatment of MCF-7 cells with physiologic levels of estrogen (1 nmol/L) induced proliferation, whereas high pregnancy levels of estrogen (100 nmol/L) induced a growth arrest of MCF-7 cells, associated with constitutive activation of extracellular signal-regulated kinase 1/2 and up-regulation of cell cycle arrest proteins such as p21waf/cip. Silencing of ANXA1 with specific small interfering RNA reverses the estrogen-dependent proliferation as well as growth arrest and concomitantly modulates extracellular signal-regulated kinase 1/2 phosphorylation. We confirm that ANXA1 is lost in clinical breast cancer, indicating that the antiproliferative protective function of ANXA1 against high levels of estrogen may be lost. Finally, we show that ANXA1-deficient mice exhibit faster carcinogen-induced tumor growth. Our data suggest that ANXA1 may act as a tumor suppressor gene and modulate the proliferative functions of estrogens. (Mol Cancer Res 2009;7(2):266–74)
CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance
Authors: Klingbeil Pamela , Marhaba Rachid , Jung Thorsten , Kirmse Robert , Ludwig Thomas , Zöller Margot 
Published: February 2009

Abstract
CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44vkd) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASMLwt) were established. ASML-CD44vkd clones hardly form lung metastases after intrafootpad application and the metastatic load in lymph nodes is significantly reduced. Rescuing, albeit at a reduced level, CD44v expression in ASML-CD44vkd cells (ASML-CD44vrsc) restores the metastatic potential. The following major differences in ASMLwt, ASML-CD44vkd, and ASML-CD44vrsc clones were observed: (a) ASMLwt cells produce and assemble a matrix in a CD44v-dependent manner, which supports integrin-mediated adhesion and favors survival. This feature is lost in the ASML-CD44vkd cells. (b) CD44v cross-linking initiates phosphatidylinositol 3-kinase/Akt activation in ASMLwt cells. Accordingly, apoptosis resistance is strikingly reduced in ASML-CD44vkd cells. The capacity to generate an adhesive matrix but not apoptosis resistance is restored in ASML-CD44vrsc cells. These data argue for a 2-fold effect of CD44v on metastasis formation: CD44v-mediated matrix formation is crucial for the settlement and growth at a secondary site, whereas apoptosis resistance supports the efficacy of metastasis formation. (Mol Cancer Res 2009;7(2):168–79)
Yin Yang 1 Modulates Taxane Response in Epithelial Ovarian Cancer
Authors: Matsumura Noriomi , Huang Zhiqing , Baba Tsukasa , Lee Paula S. , Barnett Jason C. , Mori Seiichi , Chang Jeffrey T. , Kuo Wen-Lin , Gusberg Alison H. , Whitaker Regina S. , Gray Joe W. , Fujii Shingo , Berchuck Andrew , Murphy Susan K. 
Published: February 2009

Abstract
Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function. (Mol Cancer Res 2009;7(2):210–20)
Inactivation of the MAL Gene in Breast Cancer Is a Common Event That Predicts Benefit from Adjuvant Chemotherapy
Authors: Horne Hisani N. , Lee Paula S. , Murphy Susan K. , Alonso Miguel A. , Olson John A. , Marks Jeffrey R. 
Published: February 2009

Abstract
Dysregulation of MAL (myelin and lymphocyte protein) has been implicated in several malignancies including esophageal, ovarian, and cervical cancers. The MAL protein functions in apical transport in polarized epithelial cells; therefore, its disruption may lead to loss of organized polarity characteristic of most solid malignancies. Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared with normal breast epithelial cells. Differential methylation between normal and cancer DNA was confined to the proximal promoter region. In a subset of breast cancer cell lines including T47D and MCF7 cells, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor 5-aza-2′-deoxycytidine. In addition, expression of MAL reduced motility and resulted in a redistribution of lipid raft components in MCF10A cells. MAL protein expression measured by immunohistochemistry revealed no significant correlation with clinicopathologic features. However, in patients who did not receive adjuvant chemotherapy, reduced MAL expression was a significant predictive factor for disease-free survival. These data implicate MAL as a commonly altered gene in breast cancer with implications for response to chemotherapy. (Mol Cancer Res 2009;7(2):199–209)
p53 Mutant Human Glioma Cells Are Sensitive to UV-C-Induced Apoptosis Due to Impaired Cyclobutane Pyrimidine Dimer Removal
Authors: Batista Luis F.Z. , Roos Wynand P. , Kaina Bernd , Menck Carlos F.M. 
Published: February 2009

Abstract
The p53 protein is a key regulator of cell responses to DNA damage, and it has been shown that it sensitizes glioma cells to the alkylating agent temozolomide by up-regulating the extrinsic apoptotic pathway, whereas it increases the resistance to chloroethylating agents, such as ACNU and BCNU, probably by enhancing the efficiency of DNA repair. However, because these agents induce a wide variety of distinct DNA lesions, the direct importance of DNA repair is hard to access. Here, it is shown that the induction of photoproducts by UV light (UV-C) significantly induces apoptosis in a p53-mutated glioma background. This is caused by a reduced level of photoproduct repair, resulting in the persistence of DNA lesions in p53-mutated glioma cells. UV-C-induced apoptosis in p53 mutant glioma cells is preceded by strong transcription and replication inhibition due to blockage by unrepaired photolesions. Moreover, the results indicate that UV-C-induced apoptosis of p53 mutant glioma cells is executed through the intrinsic apoptotic pathway, with Bcl-2 degradation and sustained Bax and Bak up-regulation. Collectively, the data indicate that unrepaired DNA lesions induce apoptosis in p53 mutant gliomas despite the resistance of these gliomas to temozolomide, suggesting that efficiency of treatment of p53 mutant gliomas might be higher with agents that induce the formation of DNA lesions whose global genomic repair is dependent on p53. (Mol Cancer Res 2009;7(2):237–46)