Recent studies have suggested that angiogenesis in vivo may be mediated partly by the differentiation of circulating bone marrow-derived stem cells into the endothelial cells (EC) that invest newly-forming blood vessels, but the role of this mechanism in tumor angiogenesis has not been investigated. The overall goal of this project is to characterize the importance of this novel mechanism to tumor growth. Specifically, I will employ (i) a chronic in vivo microcirculatory mod in immunodeficient mice to observe whether incorporation or transplanted bone marrow cells (BMC) into blood vessels of growing tumors occurs, as well as to gauge the importance of this mechanism relative to other possible angiogenic mechanisms: (ii) sections and/or whole-mount immunohistochemistry to verify that any incorporated BMC exhibit a vascular EC phenotype; (iii) in vitro cell sorting methods to identify which subset or subset(s) of BM cells are capable of undergoing such differentiation; and (iv) a quantitative, bioengineering analysis to provide an estimate of the angiogenesis rate in tumors, given various rates of BMC incorporation. For part (i), focal radiotherapy will be employed to restrict the availability of putative endothelial cell progenitors, but alternative means, including photodynamic therapy and chemotherapy, may be considered. A convincing identification of BMC is tumor EC progenitors may aid in the development of novel anti-angiogenic therapies for cancer treatment.
