© 2005 by the Society forNeuro-Oncology
Endogenous inhibitors of angiogenesis in malignant gliomas: Nature'santiangiogenic therapy
Departments of Pathology, Division of Neuropathology,and Cell Biology (T.A.R., C.Y.F., C.L.G.), and theMedical Scientist Training Program (T.A.R.), University of Alabama atBirmingham, Birmingham, AL 35294 USA
2 Address correspondence to Candece L. Gladson, The University of Alabama atBirmingham, LHRB 567, 701 South 19th Street, Birmingham, AL 35294, USA(gladson{at}uab.edu).
Angiogenesis is necessary for tumor growth beyond a volume of approximately2 mm3. This observation, along with the accessibility of tumorvessels to therapeutic targeting, has resulted in a research focus oninhibitors of angiogenesis. A number of endogenous inhibitors of angiogenesisare found in the body. Some of these are synthesized by specific cells indifferent organs, and others are created by extracellular proteolytic cleavageof 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 areexpressed in malignant glioma biopsies or because animal studies in malignantglioma models have suggested that their therapeutic administration could beefficacious. We review the known mechanisms of action, potential receptors,expression in glioma biopsy samples, and studies testing their potentialtherapeutic efficacy in animal models of malignant glioma. Two conclusions canbe made regarding the mechanisms of action of these inhibitors: (1) Several ofthese inhibitors appear to mediate their antiangiogenic effect throughmultiple protein-protein interactions that inhibit the function ofproangiogenic molecules rather than through a specific receptor-mediatedsignaling event, and (2) TSP-1 and TSP-2 appear to mediate theirantiangiogenic 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 ofangiogenesis in certain organs may be part of a host antitumor response. Thestudies reviewed here suggest that new antiangiogenic therapies for malignantgliomas offer exciting promise as nontoxic, growth-inhibitory agents.
Received December 10, 2004; Accepted January 28, 2005
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