期刊
MOLECULAR CANCER RESEARCH
卷 14, 期 12, 页码 1288-1299出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-16-0103
关键词
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资金
- European Research Council (ERC)
- US Department of Defense (DoD)
- Prostate Cancer Canada - Canada Safeway [RS2014-02]
- SPORE in Pancreatic Cancer (Rapid Autopsy Pancreas program) [CA127297]
- TMEN Tumor Microenvironment Network [U54 CA163120]
- NCI Cancer Center Support Grant [P30 CA36727]
- Lundbeck Foundation [R209-2015-3750] Funding Source: researchfish
Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integ-rin-beta 1 (ITGB1) and integrin-alpha 4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes beta-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. (C) 2016 AACR.
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