One of the more important recent developments in clinical oncology has been the approval of antiangiogenic drugs for the treatment of various types of cancer. We have found that these drugs not only act locally to inhibit the formation of new blood vessel capillaries in tumors, but also systemically by targeting bone marrow-derived endothelial precursor cells (CEPs). It has been suggested that other bone marrow-derived cell (BMDC) types contribute to tumor angiogenesis and growth by either directly incorporating to the vessel lumen or by residing at preivascular site - promoting angiogenesis by unknown paracrine mechanisms. With respect to CEPs, there is an ongoing controversy about their relative contribution to tumor blood vessel formation, in large due to a number of studies which reported low or even no detectable incorporation of such cells to the lumen of tumor blood vessel capillaries. We have recently shown that there are circumstances, namely, after acute cytotoxic drug therapy using vascular disrupting agents, or chemotherapy drugs including pactliaxel, 5-flourouracil, and docetaxel, where levels of CEPs are acutely mobilized from the bone-marrow niche, and subsequently colonize the drug-treated tumors, where they can make a significant contribution to tumor re-growth. These observations suggest a new perspective as for the role of CEPs in tumor angiogenesis and growth. Here, we propose to evaluate the contribution of different BMDC types to tumor angiogenesis and growth, and their contribution to metastasis seeding after treatment with cytotoxic anti-cancer drug therapies. In addition we will identify the various host factors and cytokines which promote BMDC mobilization and tumor homing. A major emphasis will be placed on new treatment strategies that can inhibit the host bone-marrow responses which contribute to tumor cell repopulation and metastasis, and as such the results could reveal new combinatorial promising treatment modalities for cancer.
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