Vivek Mittal

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 α-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.

Functional genomic and proteomic approaches have begun to revolutionize cancer research. The advent of powerful technologies, such as DNA microarrays, serial analysis of gene expression, RNA interference and proteomics, has accelerated investigations of gene identification and function at a scale never before accomplished. Approaches integrating these technologies with high-throughput forward and reverse genetic screens, are already providing insights into the mechanistic understanding of angiogenesis, leading to the identification of proteins that can be used for selective targeting of tumor vessels.