Inhibition of glypican-1 expression induces an activated fibroblast phenotype in a human bone marrow-derived stromal cell-line

Abstract

Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.

Integrating plasma proteomes with genome-wide association data for causal protein identification in multiple myeloma

“…Thus, despite being considered as a potential target for cancer therapy in some solid tumors, the actual application of targeting GPC1 has not been realized. Furthermore, new evidence suggests that GPC1 expression in bone marrow-derived stromal cells exerts inhibitory effects on cancer cells, making GPC1 a promising target for the development of anti-cancer therapies targeting fibroblast cells [ 58 ]. Nonetheless, the involvement of these proteins in MM may be substantial and merits further research attention.…”

The kinesin KIF20A promotes progression to castration-resistant prostate cancer through autocrine activation of the androgen receptor

“…In VCaP and LNCaP cells, androgen treatment promotes Endoplasmic-Reticulum-to-Golgi vesicle trafficking by increasing transcription of protein transport genes (including CREB3L2 , a transcription factor that co-localizes with AR) [ 40 ]. Additionally, CRPC cells release paracrine-acting factors that stimulate bone-derived mesenchymal stem cells and stromal cells of fibroblast lineage [ 41 , 42 ], suggesting that secretion may be advantageous for CRPC progression and tumorigenesis. Although KIF20A serves dual functions in mitosis and secretion, our data are most consistent with KIF20A’s role in secretion of factors that in the context of PC are important for CRPC progression.…”

Substrate viscoelasticity affects human macrophage morphology and phagocytosis

“…This could suggest that the HS-5 fibroblasts become mechanically activated on vPAA substrates, as activated fibroblasts are known to exhibit more elongated spindle or stellate morphologies and have larger nuclei. [26][27][28][29]…”