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Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization

¹ Cancer Genome Research Center, Cold Spring Harbor Laboratory, Woodbury, New York 11797, USA; ² Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; ³ Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; ⁴ Graduate Program in Genetics, Stony Brook University, Stony Brook, New York 11794, USA

Tumors build vessels by cooption of pre-existing vasculature and de novo recruitment of bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the contribution and the functional role of EPCs in tumor neoangiogenesis are controversial. Therefore, by using genetically marked BM progenitor cells, we demonstrate the precise spatial and temporal contribution of EPCs to the neovascularization of three transplanted and one spontaneous breast tumor in vivo using high-resolution microscopy and flow cytometry. We show that early tumors recruit BM-derived EPCs that differentiate into mature BM-derived endothelial cells (ECs) and luminally incorporate into a subset of sprouting tumor neovessels. Notably, in later tumors, these BM-derived vessels are diluted with non-BM-derived vessels from the periphery, which accounts for purported differences in previously published reports. Furthermore, we show that specific ablation of BM-derived EPCs with -particle-emitting anti-VE-cadherin antibody markedly impaired tumor growth associated with reduced vascularization. Our results demonstrate that BM-derived EPCs are critical components of the earliest phases of tumor neoangiogenesis.

[Keywords: Bone marrow transplantation; tumor angiogenesis; endothelial progenitor cells; endothelial cells; VE-cadherin; neovascularization]

Received April 5, 2007; revised version accepted April 30, 2007.

E-MAIL mittal{at}cshl.edu; FAX (516) 422-4109.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.436307

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