Paradoxical Role of Glypican-1 in Prostate Cancer Cell and Tumor Growth

Abstract

Recent studies suggest that glypican-1 (GPC-1) is a biomarker for prostate cancer, but there are few studies elucidating the role of GPC-1 in prostate cancer progression. We observed high expression of GPC-1 in more aggressive prostate cancer cell lines such as PC-3 and DU-145. While inhibition of GPC-1 expression in PC-3 cells decreased cell growth and migration in vitro , it surprisingly increased cell proliferation and migration in DU-145 cells, suggesting that the role of GPC-1 is cell type-dependent. Further, GPC-1 inhibition increased PC-3 tumor size in NCr nude mice xenografts. We hypothesized that the discrepancy between the in vitro and in vivo data is mediated by stromal cells in the tumor microenvironment. Thus, we tested the effect of tumor conditioned media (TCM) on gene expression in human mesenchymal stem cells and fibroblasts. Treatment of stromal cells with TCM from PC-3 cells transfected with GPC-1 shRNA increased the expression of migration markers, endocrine/paracrine biomolecules, and extracellular matrix components. Additionally, the decreased cell growth in GPC-1 knockdown PC-3 cells was rescued by coculturing with stromal cells. These data demonstrate the paradoxical role that GPC-1 plays in prostate cancer cell growth by interacting with stromal cells and through ECM remodeling and endocrine/paracrine signaling.

Tumor Microenvironment Uses a Reversible Reprogramming of Mesenchymal Stromal Cells to Mediate Pro-tumorigenic Effects

“…Beyond the fact that MSC effects in the tumor microenvironment depend on the interactions with the adipose tissue and malignant cells (pro-tumorigenic when there are cross-talks and anticancer effects when there are poor interactions) and with the ECM programming (pro- or anticancer) to support differences between in vitro and in vivo studies, controversies on the roles of stromal cells in the tumor microenvironment may also emerge from MSC origin and the cancer type. This hypothesis is fully supported by a report of Quach et al (2019) where the inhibition of the glypican-1 (GPC-1) prostate cancer biomarker in the aggressive prostate cancer cell line PC-3 decreased cell growth and migration in vitro , but increased PC-3 tumor size in NCr nude mice xenografts. Authors also observed that GPC-1 inhibition in an aggressive prostate cancer cell line, the DU-145 cells, increased cancer cell proliferation and migration, suggesting that GPC-1 accounts among the factors that drive cancer cell line-dependent responses to stromal cells Reduced cell growth observed in GPC-1 knockdown PC-3 cells was rescued by culturing the cells with MSCs and CAFs.…”

“…Authors also observed that GPC-1 inhibition in an aggressive prostate cancer cell line, the DU-145 cells, increased cancer cell proliferation and migration, suggesting that GPC-1 accounts among the factors that drive cancer cell line-dependent responses to stromal cells Reduced cell growth observed in GPC-1 knockdown PC-3 cells was rescued by culturing the cells with MSCs and CAFs. Further, the treatment of these stromal cells with tumor-conditioned media from PC-3 cells transfected with GPC-1 shRNA increased the expression of extracellular matrix components, endocrine and paracrine biomolecules, and migration markers ( Quach et al, 2019 ). In another study, despite in vivo observations revealing the ability of IGF/IGF-IR signaling to induce drug resistance and influence the ability to form metastasis via the induction of EMT in pancreatic cancer, the activation of this signaling pathway by stromal cells failed to induce EMT in cultures with MiaPaCa-2, AsPC-1, Capan-2, BxPC-3, and Panc1 pancreatic cancer cell lines ( Kopantzev et al, 2019 ), suggesting a key role for tumor microenvironment for the pro-tumorigenic effects of this MSC-activated signaling pathway.…”

Emerging data supporting stromal cell therapeutic potential in cancer: reprogramming stromal cells of the tumor microenvironment for anti-cancer effects

“…Experimental evidence supports the idea that stromal cell effects and origin may explain the discrepancies amongst data from in vitro and in vivo studies. Quach and colleagues 121 reported that while the inhibition of the glypican-1 (GPC-1) prostate cancer biomarker decreases cell growth and migration in vitro of the aggressive prostate cancer cell line PC-3, quite surprisingly it increases the PC-3 tumor size in NCr nude mice xenografts. Also surprisingly, it increases cancer cell proliferation and migration in aggressive prostate cancer cell line DU-145 cells, suggesting that GPC-1 accounts for among the factors that drive a cell line-dependent response to stromal cells.…”

<p>Role of αVβ3 in Prostate Cancer: Metastasis Initiator and Important Therapeutic Target</p>

“…Cells must survive in the vasculature and finally be deposited in the corresponding tissue. 12,13 Currently, a large number of in vivo and in vitro studies have found that the integrin protein family is involved in the entire process of tumor cell invasion and metastasis. 5,7,10,14 In PCa, αVβ3 is the most studied integrin during metastasis.…”