Cancer Research Annual Meeting 2010 EMT and Cancer Progression and Treatment
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[Cancer Research 63, 3403-3412, June 15, 2003]
© 2003 American Association for Cancer Research

Tumor Biology

Tumor-derived Vascular Endothelial Growth Factor Up-Regulates Angiopoietin-2 in Host Endothelium and Destabilizes Host Vasculature, Supporting Angiogenesis in Ovarian Cancer1

Lin Zhang, Nuo Yang, Jin-Wan Park, Dionyssios Katsaros, Stefano Fracchioli, Gaoyuan Cao, Ann O’Brien-Jenkins, Thomas C. Randall, Stephen C. Rubin and George Coukos2

Abramson Family Cancer Research Institute [L. Z., G. Co.], Center for Research on Reproduction and Women’s Health [L. Z., J-W. P., A. O-J., G. Co.], Division of Gynecologic Oncology, Department of Obstetrics and Gynecology [T. C. R., S. C. R., G. Co.], Cell and Molecular Biology Program and Department of Genetics [N. Y.], Division of Pulmonary, Allergy and Critical Care, Department of Medicine [G. Ca.], University of Pennsylvania, Philadelphia, Pennsylvania 19104, and Department of Obstetrics and Gynecology, University of Turin, Turin, Italy [D. K., S. F.]

Vascular remodeling in host tissues surrounding growing tumors is implicated in the successful development of tumor neovasculature. Cooperation between vascular endothelial growth factor (VEGF) and angiopoietins (Angs) is considered to be critical in this context. However, the mechanisms regulating the coordinated expression of these molecules remain, to date, elusive. In this study, we used a murine ovarian cancer angiogenesis model induced by overexpression of VEGF, as well as 52 human ovarian cancer specimens and 36 established cancer cell lines to characterize the expression and regulation of Ang-2 in the context of tumor angiogenesis. Using a combination of immunohistochemistry, laser capture microdissection and real-time quantitative reverse transcription-PCR, we showed that tumor-derived VEGF significantly up-regulated the expression of Ang-2 in host stroma endothelial cells, resulting in markedly increased Ang-2/Tie-2 mRNA copy number ratio in vivo. In vitro experiments showed that VEGF directly up-regulated Ang-2, which is mediated via VEGF receptor-2/flk-1/KDR pathway, in cultured endothelial cells through transcriptional activation rather than the enhanced mRNA stability. In human ovarian cancer, Ang-2 was primarily expressed in stroma endothelial cells and detectable in tumor cells of only 12% tumor specimens; however, it was not detected in the majority of established ovarian cancer cell lines. In addition, a significant correlation was observed between VEGF and Ang-2 mRNA expression (P < 0.01) but not between VEGF and Ang-1 or Tie-2 in human ovarian cancer specimens. In the mouse ovarian cancer model, up-regulation of Ang-2 in host stroma endothelial cells was significantly associated with pericyte loss and instability of the host vasculature surrounding the tumor. Our study suggests a novel mechanism by which tumor-derived VEGF interacts with Angs/Tie-2 system in host stroma endothelial cells and induces in a paracrine manner the remodeling of host vasculature to support angiogenesis during tumor growth.




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Copyright © 2003 by the American Association for Cancer Research.