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Abstract
Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment (TME). CAFs play an important role in orchestrating tumor-stromal interactions, and are significant contributors to cancer cell growth, metastasis, ECM remodeling, angiogenesis, immunomodulation, and chemoresistance. Despite their indisputable role in mediating cancer progression, CAFs have not been successfully targeted for the treatment of cancer. In this dissertation, we have elucidated the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating various components of the prostate cancer TME. Our data suggests that GPC-1 loss in human bone-derived stromal cells of fibroblast origin causes their activation akin to that observed in CAFs. Moreover, GPC-1 inhibition leads to augmentation of this activated phenotype when fibroblasts are exposed to prostate cancer cell conditioned media (CCM). Further investigations revealed that these fibroblasts increase prostate cancer aggressiveness after the loss of GPC-1. Collectively, our data indicates that GPC-1 plays a significant role in regulating the intrinsic and extrinsic phenotype of human bone-derived fibroblasts, presenting GPC-1 as an attractive target for developing anti-CAF therapeutics to control cancer. In addition to investigating the role of GPC-1 in regulating fibroblast activation, we have also explored the functional interaction of GPC-1 with PLA2G2A, a secretory phospholipase protein with altered expression in several cancers and inflammatory diseases. However, PLA2G2A has not been successfully targeted in clinical trials. Our data shows that GPC-1 mediates the intrinsic and extrinsic localization of PLA2G2A in prostate cancer cells, including its presence in extracellular vehicles (EVs), suggesting that GPC-1 regulates the release of PLA2G2A into the prostate cancer TME. GPC-1 also regulates the number of EVs released by prostate cancer cells. As EVs are important players in cancer-stroma communications, these data further underscore the significance of GPC-1 in mediating tumor-stroma cross-talk.