Endothelial Stem Cells in Tumor Vasculature

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Tumor growth and metastasis are absolutely dependent on the ability to recruit and sustain a functional vasculature. The study of tumor neovascularization has focused traditionally on "angiogenesis," the growth of new vessels from proliferation of existing vessels. There have been several recent studies that indicate that portions of tumor vasculature are derived by "vasculogenesis," whereby bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) home to sites of tumor growth and contribute to blood vessel formation. Vascular Endothelial Growth Factor (VEGF) and its receptors play a fundamental role in normal and abnormal angiogenesis, including tumor vascularity. However, the role of VEGF and its receptors in tumor vasculogenesis and the factors responsible for EPC recruitment to sites of neovascularization are not yet known. The overall objective of this proposal is to study the mechanism of EPC differentiation and to determine to what extent and by which mechanisms BM-derived EPCs play a role in vasculogenesis during tumor neovascularization. The experiments outlined are designed to test two hypotheses: 1) VEGF promotes tumor growth by acting as a pro-vasculogenic cytokine via its ability to recruit and promote the survival of EPCs. 2) EPCs derived from culture expanded human peripheral blood are derived from monocytes and engraft transiently. The specific aims of this proposal are: 1) To determine quantitatively and qualitatively the contribution of EPCs to the development of tumor vasculature in vivo. Specifically, what are the extent, distribution and persistence of BM-derived vasculature and how are these parameters affected by local VEGF? 2) To determine if VEGF-VEGFR1 interactions mediate the targeting of EPCs to site of tumor growth in vivo by using receptor-specific antibodies and overexpressing VEGFR1 in EPCs. 3) To compare homing and persistence of BM-progenitor (CD34+/lin-) EPCs and culture-expanded EPCs in tumor vasculogenesis and to determine if EPC differentiation occurs through a monocyte intermediate using transgenic mouse models. The proposed experiments and training plan are designed to help me develop into an excellent physician scientist. I hope that significant contributions to the study of stem cells will result in the establishment of a successful, independent research program.