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Tumor Vascular Proteins As Biomarkers in Ovarian Cancer

Ronald J. Buckanovich, Dimitra Sasaroli, Anne O'Brien-Jenkins, Jeffrey Botbyl, Rachel Hammond, Dionysios Katsaros, Raphael Sandaltzopoulos, Lance A. Liotta, Phyllis A. Gimotty, George Coukos

From the Center for Research on Reproduction and Women's Health, Abramson Family Cancer Research Institute, Department of Medicine Division of Hematology-Oncology, and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA; University of Michigan, Ann Arbor, MI; Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA; Department of Obstetrics and Gynecology, University of Turin, Turin, Italy; and Molecular Biology and Genetics Program, Democritus University of Thrace, Komotini, Greece

Address reprint requests to George Coukos, MD, PhD, 1315 BRB II/III, 421 Curie Blvd, Philadelphia, PA, 19104; e-mail: gcks{at}mail.med.upenn.edu

Purpose: This study aimed to identify novel ovarian cancer biomarkers and potential therapeutic targets through molecular analysis of tumor vascular cells.

Methods: Immunohistochemistry-guided laser-capture microdissection and genome-wide transcriptional profiling were used to identify genes that were differentially expressed between vascular cells from human epithelial ovarian cancer and healthy ovaries. Tumor vascular markers (TVMs) were validated through quantitative real-time polymerase chain reaction (qRT-PCR) of immunopurified tumor endothelial cells, in situ hybridization, immunohistochemistry, and Western blot analysis. TVM expression in tumors and noncancerous tissues was assessed by qRT-PCR and was profiled using gene expression data.

Results: We identified a tumor vascular cell profile of ovarian cancer that was distinct from the vascular profile of normal ovary and other tumors. We validated 12 novel ovarian TVMs. These were expressed by immunopurified tumor endothelial cells and localized to tumor vasculature. Select TVMs were found to be specifically expressed in ovarian cancer and were absent in all normal tissues tested, including female reproductive tissues with physiologic angiogenesis. Many ovarian TVMs were expressed by a variety of other solid tumors. Finally, overexpression of any one of three ovarian TVMs by vascular cells was associated with decreased disease-free interval (all P < .005).

Conclusion: We have identified for the first time the molecular profile of ovarian tumor vasculature. We demonstrate that TVMs may serve as potential biomarkers and molecular targets for ovarian cancer and a variety of other solid tumors.

Supported by National Institutes of Health (NIH) Grant No. R01 CA098951; National Cancer Institute (NCI) Ovarian Cancer Specialized Program of Research Excellence (SPORE) Grant No. P50-CA083638; US Army Medical Research and Materiel Command Grant No. OC-050314; and the Marcia and Philip Rothblum Foundation. R.J.B. was supported by NIH/National Institute of Child Health and Human Development Grant No. K12-HD43459 and the Ovarian Cancer Research Fund. The laser-capture microdissection facility was supported by a generous grant by the Fannie Rippel Foundation.

R.J.B and D.S. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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