Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy whose growth, like that of all solid cancers, is dependent on neovascularization. The mechanism by which tumors induce a neovascular response is considered to be through angiogenesis: the process of new blood vessel formation from pre-existing ones. However, new blood vessels can also form through vasculogenesis, in which vessels from de novo by the assembly of precursor cells, including CD34 positive hematopoietic progenitor cells. Past work by the investigator had shown that HNSCC tumor cells mobilize CD34 positive hematopoietic progenitor cells, leading to increased levels of these cells in the periphery and within the tumor mass. They hypothesize that HNSCC stimulate neovascularization not only by angiogenesis, but also by vasculogenesis through the chemoattraction of CD34 positive cells and the induction of their differentiation into endothelial cells that become incorporated into the newly formed vasculature of the tumor. This hypothesis will be tested in vitro with primary HNSCC cultures and CD34+ progenitor cells isolated from blood of HNSCC patients and umbilical cords, and in vivo in a human HNSCC xenogeneic model through the following specific aims: To identify the HNSCC-derived factors that chemoattract CD34 positive progenitor cells (Aim 1) and induce their differentiation into endothelial cells (Aim 2). To determine in vivo if tumors attract CD34 positive progenitor cells as well as induce their differentiation into endothelial cells of the newly formed tumor vasculature (Aim 3). These studies will also determine if blocking the CD34+ cell chemoattraction or diversion to endothelial cell differentiation can block HNSCC-induced vasculogenesis. The proposed studies are expected to show that vasculogenesis contributes to tumor neovascularization. In addition, these studies may provide insights into therapies that can block tumor-induced vasculogenesis which, when included with strategies to block angiogenesis, can result in a more comprehensive therapeutic approach to blocking tumor vascularization.
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