Characterizing and Targeting Tumoral Factors Recruiting Perivascular Progenitors

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LONG-TERM OBJECTIVES AND SPECIFIC AIMS: Recent evidence suggests that tumor endothelium and pericytes, cells which wrap around blood vessels, can arise from either circulating marrow-derived progenitors or from more mature cells in the tumor cavity. The central hypothesis of this proposal is that glioblastoma-secreted factors regulate the recruitment of marrow-derived perivascular progenitor cells, and that a therapeutic strategy targeting these factors recruiting marrow-derived and locally-derived endothelium and pericytes will significantly impede the growth of xenografts derived directly from human glioblastomas without passaging in culture, an animal model that recapitulates the invasiveness and vascularity of human glioblastoma. Our specific aims will be: (1) To characterize marrow-derived and locally-derived pericytes in human glioblastoma xenografts, particularly tumor-secreted factors leading to recruitment of each pericyte type; (2) To characterize tumor-secreted factors influencing the number of intratumoral and circulating marrow-derived perivascular progenitor cells and identify biomarkers of therapies targeting pericytes; and (3) To determine the effects of combined treatment targeting vasculogenesis, angiogenesis, and locally and marrow-derived pericytes in vivo in human glioblastoma xenografts. PUBLIC DESCRIPTION IN LAY LANGUAGE: The median survival for glioblastoma patients has remained poor and unchanged over the past decade, at 12-13 months. Among the causes of this poor prognosis is the rich vascularity of glioblastoma, a defining feature. This proposal describes a series of experiments designed to uncover the mechanisms by which glioblastoma acquires its uniquely rich vascularity. In particular, we will identify tumor-secreted factors that lead to the recruitment of endothelial cells, the cells that line the blood vessels, and pericytes, the cells on the outside of the blood vessels that provide nourishment to endothelium. By studying recruitment of endothelium and pericytes from local intratumoral sources and from circulating bone marrow-derived precursor cells, we hope to obtain a comprehensive understanding of how glioblastoma acquires its uniquely rich vasculature, which will be essential to designing RELEVANCE (See instructions): Glioblastoma is a malignant brain tumor in which the average patient survivals barely over one year from the time of diagnosis. The rich blood supply of glioblastoma is believed to contribute to this poor prognosis. This proposal seeks to uncover and therapeutically target the unique mechanisms by which glioblastoma acquires its rich blood supply.