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Tumor Stromal-Derived Factor-1 Recruits Vascular Progenitors to Mitotic Neovasculature, where Microenvironment Influences Their Differentiated Phenotypes

¹ Program in Neurosurgery, Massachusetts General Hospital and Harvard Medical School; ² Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts and ³ Department of Neurological Surgery, Dardinger Laboratory for Neuro-Oncology and Neurosciences, Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio

Requests for reprints: E. Antonio Chiocca, Department of Neurological Surgery, The Ohio State University Medical Center, James Cancer Hospital and Solove Research Institute, N-1017 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-9312; Fax: 614-293-4024; E-mail: EA.Chiocca{at}osumc.edu or David T. Scadden, Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA. Phone: 617-726-5615; Fax: 617-724-2662; E-mail: Dscadden{at}Partners.org.

Mechanisms underlying tumor vasculogenesis, the homing and engraftment of bone marrow–derived vascular progenitors, remain undefined. We hypothesized that tumor cell–secreted factors regulate vasculogenesis. We studied vasculogenic and nonvasculogenic intracranial murine gliomas. A PCR screen identified stromal-derived factor-1 (SDF-1/CXCL12) and vascular endothelial growth factor (VEGF) expression by vasculogenic glioma cells and spontaneously arising vasculogenic tumors in NF1^+/–:Trp53^+/– mice, but not by nonvasculogenic glioma cells. Enforced SDF-1, not VEGF, expression in nonvasculogenic cells caused vasculogenesis. Combined SDF-1 and VEGF expression augmented vasculogenesis over SDF-1 expression alone. Blocking SDF-1 receptor CXCR4 reduced short-term homing and long-term engraftment of vascular progenitors. Implanting tumor cells secreting SDF-1 was therefore necessary and sufficient to incorporate marrow-derived precursors into tumor endothelium. SDF-1 seemed to exert these effects by acting locally intratumorally and did not cause an efflux of marrow-derived progenitors into circulation. Tumor microenvironment determined additional fates of marrow-derived cells. Hypoxia, observed with ectopic s.c. murine tumors at levels approximating that of intracranial human glioblastoma, interacted with tumor-secreted SDF-1 to expand engrafted vascular progenitor differentiated phenotypes to include pericytes as well as endothelium. In contrast, less hypoxic orthotopic intracranial murine gliomas contained only marrow-derived endothelium without marrow-derived pericytes. Furthermore, we found that vasculogenesis is significant for tumors because it generates endothelium with a higher mitotic index than endothelium derived from local sources. Although CXCR4 blockade selectively targeted endothelium generated by vasculogenesis, completely inhibiting vessel formation may require combination therapy targeting locally derived and marrow-derived endothelium. (Cancer Res 2006; 66(18): 9054-64)

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