Despite multiple changes in the chemotherapeutic approach for Ewing's sarcoma, the 2 year disease-free survival remains at 40-50% depending on disease site. Better understanding of the tumor biology may uncover therapeutic approaches. Using a nude mouse model, we demonstrated that Ewing's sarcoma cells overexpress VEGF and that bone marrow stem cells contribute to the development of new tumor vasculature as the tumor grows (a process known as vasculogenesis as opposed to angiogenesis). Approximately 10% of the new tumor vessels could be attributed to vasculogenesis. We further demonstrated the chemotactic capability of VEGF for bone marrow cells both in vitro (using Boyden Chambers) and in vivo (using matrigel-VEGF plugs). Together these data suggest that bone marrow cells travel to the tumor area in response to VEGF and subsequently contribute to the expansion of the tumor vasculature that is required to support the growing tumor. Our goal is to determine whether VEGF is the chemotactic stimulus, if suppressing VEGF has an impact on bone marrow cell migration and subsequent tumor vasculogenesis, and finally whether these bone marrow cells can be modified to deliver genes to the tumor area. We propose to (1) define the bone marrow cell subpopulations that contribute to this vasculogenesis process. (2) Determine whether cell division of migrated bone marrow cells contributes to vasculogenesis. (3) Determine whether tumor VEGF165 production influences tumor vasculogenesis. This will be done by inhibiting VEGF165 by siRNA. (4) Determine whether CD34+ (or mesenchymal cells as an alternative) can be used to deliver genes to the tumor area. Understanding the biology and the role that vasculogenesis plays in the development of Ewing's sarcoma may provide new therapeutic targets. Our goal is to identify whether VEGF165 is the chemotactic signal, to determine whether interfering with VEGF165 has an impact on the migration of bone marrow cells and explore whether these cells can be used to deliver genes to the tumor area.
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