title: CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers.
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.
authors.affiliation: Tulane University Health Science Center, New Orleans, LA 70112, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.forename: Andrzej
authors.initials: A
authors.lastname: Lange
authors.forename: Peter
authors.initials: P
authors.lastname: Mottram
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Pui
authors.initials: P
authors.lastname: Cheng
authors.forename: Melina
authors.initials: M
authors.lastname: Hogan
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.forename: Linhua
authors.initials: L
authors.lastname: Zou
authors.forename: Véronique
authors.initials: V
authors.lastname: Machelon
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
authors.forename: Margarita
authors.initials: M
authors.lastname: Terrassa
authors.forename: Andrew
authors.initials: A
authors.lastname: Lackner
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D001201:Ascites / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A