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Angiogenesis is the formation of new blood vessels from the existing vasculature and is necessary for tumor growth. Syndecan-2 (S2) is highly expressed in the microvasculature of mouse gliomas. When S2 expression was down-regulated in mouse brain microvascular endothelial cells (MvEC), this inhibited cell motility and reduced the formation of capillary tube-like structures in vitro. Pro-angiogenic growth factors and enzymes up-regulated during glioma tumorigenesis stimulated shedding of the S2 ectodomain from endothelial cells in vitro. The effect of shed S2 on angiogenic processes was investigated by incorporating recombinant S2 ectodomain (S2ED) into in vitro angiogenesis assays. S2ED promoted membrane protrusion, migration, capillary tube formation, and cell-cell interactions. We therefore propose that S2 is necessary for angiogenesis of MvEC, proangiogenic factors expressed during glioma progression regulate S2 shedding, and shed S2 ectodomain may increase endothelial cell angiogenic processes.Syndecan-2 is one of a family of transmembrane heparan sulfate proteoglycans. Syndecan-1, -2, -3, and -4 (S1, S2, S3, S4) 2 have divergent ectodomains with covalently bound heparan sulfate glycosaminoglycan chains, conserved transmembrane domains, and short cytoplasmic tails (1). The ectodomains can be shed from the cell surface both constitutively and in response to stress or injury, although the precise mechanism is not known (2, 3). The cytoplasmic tails contain conserved sequences (C1 and C2), which mediate interactions with the actin cytoskeleton and PDZ domain-containing proteins, respectively (1). Located between the C1 and C2 domains is the variable (V) region (1); the function of this domain in S1 and S3 is not known. The V region in syndecan-4 is pivotal in focal adhesion formation in fibroblasts (4, 5). The V domain in S2 regulates laminin and fibronectin matrix assembly in Chinese hamster ovary-K1 cells (6) and left-right asymmetry in Xenopus (7).Syndecan-2 may modulate tumorigenesis. Its expression is increased in human ovarian carcinoma biopsies (8) and in various cancer cell lines, and it can modulate colon cancer cell adhesion, motility, and proliferation (9 -12). Overexpression in colorectal cancer-derived cells decreased cell-cell interactions, increased lamellipodial and filopodial membrane protrusions, and increased motility (13), and competitive inhibition of S2 with a recombinant S2 ectodomain decreased cancer cell growth on soft agar and reduced cell adhesion (10). Similarly, a reduction in S2 expression by antisense cDNA in colon cancer cells inhibited anchorage-independent growth (14).Syndecan-2 is expressed by the cells of the vasculature (1), and a deficiency in S2 inhibits developmental angiogenesis in zebrafish (15). Angiogenesis is the formation of new blood vessels from the existing vasculature and is necessary for tumor growth. Syndecan-2 interacts with cytokines and growth factors that stimulate angiogenesis (e.g. interleukin-8, VEGF, bFGF, and TGF␤) and, in the case of VEGF, can potent...

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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.

Host antiangiogenesis factors defend against tumor growth. The matricellular protein, thrombospondin-2 (TSP-2), has been shown to act as an antiangiogenesis factor in a carcinogen-induced model of skin cancer. Here, using an in vivo malignant glioma model in which the characteristics of the tumors formed after intracerebral implantation of GL261 mouse glioma cells are assessed, we found that tumor growth and microvessel density were significantly enhanced in tumors propagated in TSP-2 À/À mice. Mechanistically, matrix metalloproteinase (MMP)-2 has been associated with neoangiogenesis and it has been proposed that the levels of available MMP-2 may be down-regulated by formation of a complex with TSP-2 that is internalized by low-density lipoprotein receptorrelated protein 1 (LRP1). We found elevated expression of MMP-2 and MMP-9 in tumors propagated in TSP-2 À/À mice, with a preferential localization in the microvasculature. In wild-type mice, MMP-2 was coexpressed with TSP-2 in the tumor microvasculature. In vitro, addition of recombinant (rec) TSP-2 to mouse brain microvessel endothelial cells reduced MMP-2 levels and invasion through mechanisms that could be inhibited by a competitive inhibitor of ligand binding to LRP1 or by siLRP1. Thus, the antiangiogenic activity of TSP-2 is capable of inhibiting the growth of gliomas in part by reducing the levels of MMP-2 in the tumor microvasculature. This mechanism is mediated by LRP1. (Cancer Res 2005; 65(20): 9338-46)