A Secreted Type of β1,6-N-Acetylglucosaminyltransferase V (GnT-V) Induces Tumor Angiogenesis without Mediation of Glycosylation

Abstract

Angiogenesis is the first regulatory step of tumor progression. Herein, we report on some findings that show that ␤1,6-N-acetylglucosaminyltransferase V (GnT-V) functions as an inducer of angiogenesis that has a novel and completely different function from the original function of glycosyltransferase. A secreted type of GnT-V protein itself promoted angiogenesis in vitro and in vivo at physiological concentrations. The highly basic domain of GnT-V induced the release of fibroblast growth factor-2 from heparan sulfate proteoglycan on the cell surface and/or extracellular matrix, leading to angiogenesis. These findings provide some novel information on the relationship between GnT-V and tumor metastasis. The inhibition of GnT-V secretion or its expression represents a novel potential strategy for the inhibition of tumor angiogenesis.Angiogenesis represents an obligatory step in cancer progression (1, 2). A variety of factors, such as fibroblast growth factor-2 (FGF-2), 1 vascular endothelial growth factor (VEGF) and interleukin-8, contribute to tumor growth. The production of these factors and cytokines is controlled by complicated mechanisms, which include increased gene expression, posttranslational modifications, and interactions with the extracellular matrix.Many growth factors and their receptors, some of which play a role in tumor angiogenesis, are glycoproteins. Recent studies employing glycosyltransferase gene manipulation have revealed that changes in the oligosaccharide structure of these receptors bring about alterations in intracellular signaling, thus leading to cellular transformation (3-6). ␤1,6-N-acetylglucosaminyltransferase V (GnT-V or mannoside acetylglucosaminyltransferase 5 (Mgat5)), which catalyzes the formation of ␤1-6 branching on N-glycans, has been proposed as one of the most important glycosyltransferases associated with tumor metastasis (7,8). Furthermore, a recent study of GnT-V-deficient mice indicates that it is essential for tumor metastasis as well as for tumor growth (9).Clinical studies have shown increases in GnT-V activity in breast and hepatocellular carcinomas (10, 11). In human breast cancer cells, a positive correlation was observed between GnT-V activity and tumor size (11). We have found that the expression of GnT-V in human colon cancer tissues was correlated with a poor prognosis and distant metastasis (12). This suggests that GnT-V level should be indicative of a poor prognosis in cases of colorectal cancer. These results strongly suggest that GnT-V plays a pivotal role in tumor malignancy. However, the detailed mechanisms of the regulation via GnT-V with respect to tumor size or metastasis remain unknown.To address this issue, we established GnT-V transfectants and examined the metastatic potentials of these cells. In the course of this study, we found that GnT-V transfectants induced dramatic increase in angiogenic activity. The induction of tumor angiogenesis by GnT-V is thought to be due to 1) increases in the expression/production of angiogenic factors, 2) changes...

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