Angiogenesis is necessary for
tumor growth beyond a volume of approximately 2 mm(3). 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.