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Endogenous inhibitors of angiogenesis in malignant gliomas: Nature's antiangiogenic therapy

Departments of Pathology, Division of Neuropathology, and Cell Biology (T.A.R., C.Y.F., C.L.G.), and the Medical Scientist Training Program (T.A.R.), University of Alabama at Birmingham, Birmingham, AL 35294 USA

² Address correspondence to Candece L. Gladson, The University of Alabama at Birmingham, LHRB 567, 701 South 19th Street, Birmingham, AL 35294, USA (gladson{at}uab.edu).

Abstract

Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm³. This observation, along with the accessibility of tumor vessels to therapeutic targeting, has resulted in a research focus on inhibitors of angiogenesis. A number of endogenous inhibitors of angiogenesis are found in the body. Some of these are synthesized by specific cells in different organs, and others are created by extracellular proteolytic cleavage of plasma-derived or extracellular matrix-localized proteins. In this review, we focus on angiostatin, endostatin, PEX, pigment epithelial-derived factor, and thrombospondin (TSP)-1 and -2, either because these molecules are expressed in malignant glioma biopsies or because animal studies in malignant glioma models have suggested that their therapeutic administration could be efficacious. We review the known mechanisms of action, potential receptors, expression in glioma biopsy samples, and studies testing their potential therapeutic efficacy in animal models of malignant glioma. Two conclusions can be made regarding the mechanisms of action of these inhibitors: (1) Several of these inhibitors appear to mediate their antiangiogenic effect through multiple protein-protein interactions that inhibit the function of proangiogenic molecules rather than through a specific receptor-mediated signaling event, and (2) TSP-1 and TSP-2 appear to mediate their antiangiogenic effect, at least in part, through a specific receptor, CD36, which initiates the antiangiogenic signal. Although not proven in gliomas, evidence suggests that expression of specific endogenous inhibitors of angiogenesis in certain organs may be part of a host antitumor response. The studies reviewed here suggest that new antiangiogenic therapies for malignant gliomas offer exciting promise as nontoxic, growth-inhibitory agents.

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