Oncofetal Chondroitin Sulfate Glycosaminoglycans Are Key Players in Integrin Signaling and Tumor Cell Motility.

摘要: Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, role of ofCS in cancer is largely unknown. The function was analyzed using recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from malaria parasite, Plasmodium falciparum. We demonstrate that plays a key tumor cell motility by affecting canonical integrin signaling pathways. Binding rVAR2 cells inhibited interaction extracellular matrix (ECM) components, correlated decreased phosphorylation Src kinase. Moreover, binding migration, invasion, and anchorage-independent growth vitro. Mass spectrometry ofCS-modified proteoglycan complexes affinity purified lines on columns revealed an overrepresentation proteins involved signaling, such as integrin-β1 (ITGB1) integrin-α4 (ITGA4). Saturating concentrations downstream mimicked knockdown core synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) N-acetylgalactosaminyltransferase (CSGALNACT1). modification highly expressed both human murine metastatic lesions situ preincubation or early intravenous treatment seeding spreading mice. This associated significant increase survival animals. These data functionally link modifications further highlights novel therapeutic target. Implications: cancer-specific expression aids phenotypes candidate target for therapy. Mol Cancer Res; 14(12); 1288–99. ©2016 AACR.