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Use of BOEC for Cancer Gene Therapy
New vessel formation is necessary for tumor growth and spread. Until recently neovascularization was thought to be solely dependent on proliferation and migration of preexisting, differentiated endothelial cells from neighboring vessels, i.e., angiogenesis. Recent findings suggest that circulating endothelial cell progenitors may home to sites undergoing physiological, pathological, and neoplastic changes and there they differentiate into mature endothelial cells in a process consistent with postnatal vasculogenesis. Based on our preliminary data, blood out growth endothelial cells (BOEC) expanded ex-vivo are found within the endothelium of tumor vasculature, we posit that the homing behavior of these cells can be exploited to deliver anticancer therapy. We will address the hypotheses through three specific aims. First we will identify BOEC localization in MMTV neu transgenic mice that develop spontaneous breast cancer. Secondly, we will engineer BOEC to produce cancer growth inhibitors; thrombospondin-1, sFlt-1, and sTie2. In the third specific aim we will ascertain whether engineered BOEC could inhibit tumor growth and spread in vivo. We will evaluate this hypothesis by examining engineered BOECs ability to inhibit vessel formation within the tumor in vivo and interfere with breast cancer growth and metastases. If engineered BOEC decrease tumor growth in animal model we will proceed with preparations for studies in patients with breast cancer.
Cancer requires adequate blood vessel supply in order to grow and spread. The process of new vessel formation within cancer tumor is dependent on growth of neighboring vessels and aided by circulating in blood endothelial cells that are attracted to areas of body that need increased oxygen and nutrients supply. We have proven the tumor-searching behavior of these circulating endothelial cells cultured ex-vivo and called BOEC (blood outgrowth endothelial cells). We then postulated that these cells can be used to deliver anti-cancer therapy. We have genetically engineered BOEC to produce endostatin, a substance that has ability to decrease tumor blood supply. When the cells producing the drug endostatin (EBOEC) were injected through vein into mice with tumors, they found cancer tumor and slowed new vessel formation within it. This resulted in smaller tumors than in mice given un-engineered BOEC. We therefore suggest that we can exploit BOEC to deliver anti-cancer therapy and plan in this proposal to prove it in murine model of breast cancer by using engineered BOEC producing other potent angiogenesis inhibitors.