CXCL12 and vascular endothelial growth factor synergistically induce neonaniogenisis in human ovarian cancers

Ilona Kryczek, Andrzej Lange, Peter Mottram, Xavier Alvarez, Pui Cheng, Melina Hogan, Lieve Moons, Shuang Wei, Linhua Zou, Véronique Machelon, Dominique Emilie, Margarita Terrassa, Andrew Lackner, Tyler J. Curiel, Peter Carmeliet, Weiping Zou

Research output: Contribution to journalArticle

325 Scopus citations

Abstract

Ovarian carcinomas have a poor prognosis, often associated with multifocal i.p. dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites and tumors of patients with untreated ovarian carcinoma. We observed that malignant ascites fluid induced potent in vivo neovascularization in Matrigel assay. We detected a sizable amount of vascular endothelial cell growth factor (VEGF) in malignant ascites. However, pathologic concentration of VEGF is insufficient to induce in vivo angiogenesis. We show that ovarian tumors strongly express CXC chemokine stromal-derived factor (SDF-1/CXCL12). High concentration of CXCL12, but not the pathologic concentration of CXCL12 induces in vivo angiogenesis. Strikingly, pathologic concentrations of VEGF and CXCL12 efficiently and synergistically induce in vivo angiogenesis. Migration, expansion, and survival of vascular endothelial cells (VEC) form the essential functional network of angiogenesis. We further provide a mechanistic basis for explaining the interaction between CXCL12 and VEGF. We show that VEGF up-regulates the receptor for CXCL12, CXCR4 expression on VECs, and synergizes CXCL12-mediated VEC migration. CXCL12 synergizes VEGF-mediated VEC expansion and synergistically protects VECs from sera starvation-induced apoptosis with VEGF. Finally, we show that hypoxia synchronously induces tumor CXCL12 and VEGF production. Therefore, hypoxia triggered tumor CXCL12 and VEGF form a synergistic angiogenic axis in vivo. Hypoxia-induced signals would be the important factor for initiating and maintaining an active synergistic angiogeneic pathway mediated by CXCL12 and VEGF. Thus, interrupting this synergistic axis, rather than VEGF alone, will be a novel efficient antiangiogenesis strategy to treat cancer.

Original languageEnglish (US)
Pages (from-to)465-472
Number of pages8
JournalCancer Research
Volume65
Issue number2
StatePublished - Jan 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kryczek, I., Lange, A., Mottram, P., Alvarez, X., Cheng, P., Hogan, M., Moons, L., Wei, S., Zou, L., Machelon, V., Emilie, D., Terrassa, M., Lackner, A., Curiel, T. J., Carmeliet, P., & Zou, W. (2005). CXCL12 and vascular endothelial growth factor synergistically induce neonaniogenisis in human ovarian cancers. Cancer Research, 65(2), 465-472.