UBC Theses and Dissertations
Investigating the role of oncofetal chondroitin sulfate in cancer biology and optimizing rVAR2 technology for cancer Wang, Chris Kedong
Chondroitin sulfate (CS) is a glycosaminoglycan that can be attached to membrane proteins on the cell surface to form chondroitin sulfate proteoglycans (CSPG). CSPGs are highly expressed in the placenta and associated with the ability of the placenta to maintain a high rate of proliferation, angiogenesis, as well as invasion of the uterine tissue. CSPG alterations are also described in cancers and have been associated with progression and poor patient outcomes. Our lab has discovered that placenta and cancer cells express a common CS modification named oncofeatal CS (ofCS) that can be detected by the malarial lectin VAR2CSA. Using recombinant VAR2 proteins (rVAR2), we developed a new technology to detect and target solid tumors. As a component of this technology, the effect of rVAR2 on cancer cells as well as its fate inside the cancer cells needs to be established. Therefore, I hypothesized that rVAR2 binding to cancer cells would affect intracellular signaling pathways and cellular behavior. I aspired to support the development of the rVAR2 technology through three research aims: 1) Investigate the effects of rVAR2 binding to cancer cells. I showed that rVAR2 binding induced NF-κB pathway activation and cytokine expression. 2) Characterize the cellular fate of rVAR2 after binding to cancer cells. I established that rVAR2 internalize though different pathways into the early endosomes without reaching lysosomes. 3) Establishing an rVAR2-based exosome-detection strategy. I evaluated rVAR2 as a tool to isolate cancer derived exosomes and showed its limitation. Overall, the data generated in my research have advanced our knowledge on ofCS in cancer biology and informed ongoing rVAR2 based therapeutic development.
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