Syndecan-2 Is Expressed in the Microvasculature of Gliomas and Regulates Angiogenic Processes in Microvascular Endothelial Cells

Abstract

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...

Altered expression patterns of syndecan-1 and -2 predict biochemical recurrence in prostate cancer

“…Syndecan-2 may undergo shedding, and the corresponding ectodomain may be acting as an angiogenic factor in gliomas. 24 In addition, overexpression of syndecan-2 in colon cancer cells has been associated with downregulation of E-cadherin, a long-recognized feature of the epithelial-mesenchymal transition. 12 However, the mechanisms involved in the cytoplasmic overexpression of syndecan-2 and the metastatic process remain unclear.…”

Syndecan-2 Regulates the Migratory Potential of Melanoma Cells

“…Reduction in syndecan-2 expression induces cells to switch from the transformed phenotype to flattened monolayers (8) and reduces tumorigenic activity in colon adenocarcinoma and fibrosarcoma cells (8,16). In addition, syndecan-2 is highly expressed in the microvasculature of mouse gliomas and has been shown to regulate angiogenesis in microvascular endothelial cells (17). On the other hand, an inverse correlation between syndecan-2 expression and metastatic potential has been found in Lewis lung carcinoma cell lines (6).…”

DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis

“…Two of the three genes selected from this cohort, SDC2 (FAM129A) and TMTC1, suppressed the growth of T98 GBM cells in vitro. SDC2 is a member of syndecan proteoglycan family and has been shown to be expressed differentially in several different types of cancers Kim et al, 2003;Han et al, 2004;Kusano et al, 2004;Modrowski et al, 2005;Essner et al, 2006;Fears et al, 2006). These reports have implicated SDC2 as a potential tumor suppressor gene with growth inhibitory properties.…”