The Role And Mechanism Of β1,4-galactosyltransferase V During Differentiation Of Brain Tumor-initiating Cells Into Vascular Endothelial Cells

Brain tumors are the most common and lethal type of primary tumor in central neural system, among which glioblastoma multiforme(GBM) is the most malignant. More reports have identified the chemoresistance and radioresistance of GBM, the median survival of patients diagnosed with GBM is only12-15months. Studies have shown that blood supply is required by not primary tumor but metastasis tumor, which ensures the delivery of oxygen, nutrients, and growth factors. Now many antiangiogenic therapies have been used in clinical trials, which can be considered one of the most promising treatments. But now, angiogenesis inhibitor can not inhibit tumor perfectly, even inducing aggression after antiangiogenic therapy. It required further investigation to angiogenesis and its mechanism. Recent studies have shown that glioma results from unregulated expansion of a self-renewing cells population, called glioma-initiating cells, which can be contributed to solid tumor angiogenesis, metastasis, and resistance to chemotherapy and radiotherapy. It has been reported that glioma-initiating cells have the ability to differentiate into endothelial cells.β1,4-galactosyltransf erase V is a member of β1,4-galactosyltransferase family, which has been cloned in1998. It has been reported that expression of β1,4-galactosyltransferase V is increased in the process of glioma, and β1,4-galactosyltransferase V can regulate self-renewal of glioma-initiating cell. We find that reduction in the expression of β1,4-galactosyltransferase V resulted in a total suppression of tumor growth in mouse, following with reduced angiogenesis in xenograft. And we got the same result when we repeat it with human glima-initiating cells in nude mice. In vitro reduction in the expression of β1,4-galactosyltransferase V can suppress differentiation of gioma-initiating cell into endothelial cells. The above results inspired us that β1,4-galactosyltransferase V can regulate the differentiation of gioma-initiating cell into endothelium.Further investigation reveals that Notchl participates in the process, during β1,4-galactosyltransferase V regulate the differentiation of gioma-initiating cell into endothelium. And the reduction in the expression of β1,4-galactosyltransf erase V can inhibit activated TACE clearly, which mediate the cleavage of Notchl. So we rescue the Notchl intracellular domain (ICN1) in the β1,4-galactosyltransferase V-inhibited cells, the result is that angiogenesis is up-regulated in the tumor xenografts. So we get the conclusion that β1,4-galactosyltransferase V can regulate the differentiation of glioma-initiating cells into endothelium through TACE-mediated cleavage of Notchl, providing a new therapeutic target for glioma.