Studies examining the biological pathways used by tumors to sustain and augment their growth will further our understanding of cancer and identify novel therapeutic targets. Our long-range goal is to improve our comprehension of molecular and biological mechanisms leading to the malignant progression of human gliomas. Malignant gliomas represent 40% of primary CNS tumors and have average survival rates of less than a year. This application is a competitive renewal of an application in which the goals were to broadly examine the role of the IL-8, TSP-1 and BAI-1 angiogenesis modulators in astrocytoma progression and therapy. In this renewal application we propose to continue this line of investigation with an exclusive in depth analysis of Brain Angiogenesis lnhibitor-1 function in tumor formation. Our accumulated data support an important function for this receptor as a specific physiological inhibitor of angiogenesis in the brain whose expression is lost during brain tumor formation. We discovered that the extracellular domain of BAH is cleaved, and results in the release of two extracellular fragments, which we named Vasculostatins (Vstat), because of their paracrine anti-angiogenic activities. This study will focus on three important novel aspects of BAI1 function.
Aim 1 will study the mechanism by which BAI1 gene expression is lost in the tumors, with special emphasis on epigenetic mechanisms. Preliminary data suggests the involvement of DNA methylation in BAI1 gene silencing.
Aim 2 will determine the mechanisms by which Vstats mediate the anti-angiogenic and anti-tumorigenic properties of BAI1, and their therapeutic potential for brain tumors.
Aim 3 will identify the protease that cleaves BAI1 to release Vstat-40. The anticipated result of these studies is a functional and mechanistic evaluation of the importance of BAI-1 and its cleavage fragments in brain tumor angiogenesis and tumor growth. It is our expectation that BAI1 and its Vstat fragments are integral components of a physiological mechanism that controls angiogenesis in the brain, a finding with important implications for all vascular disorders in the brain. Therapeutic use of Vstats as anti-angiogenic agents could be exploited by exogenous delivery, stimulation of their release from the endogenous BAI1 pools in the brain and through reactivation of BAI1 expression using existing epigenetic modulators. Improving the treatment of malignant gliomas, an incurable disease, is an important human health goal. ? ? ?
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