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SFRP1 induces a stem cell phenotype in prostate cancer cells.

ABSTRACT: Prostate cancer (PCa) ranks second in incidence and sixth in deaths globally. The treatment of patients with castration-resistant prostate cancer (CRPC) continues to be a significant clinical problem. Emerging evidence suggests that prostate cancer progression toward castration resistance is associated with paracrine signals from the stroma. SFRP1 is one of the extracellular proteins that modulate the WNT pathway, and it has been identified as a mediator of stromal epithelium communication. The WNT pathway is involved in processes such as cell proliferation, differentiation, cell anchoring, apoptosis, and cell cycle regulation as well as the regulation of stem cell populations in the prostatic epithelium. In the present study, we explored the role of exogenous SFRP1 on the stem cell phenotype in prostate cancer. The results reveal that cancer stem cell markers are significantly increased by exogenous SFRP1 treatments, as well as the downstream target genes of the Wnt/-catenin pathway. The pluripotent transcription factors SOX2, NANOG, and OCT4 were also up-regulated. Furthermore, SFRP1 promoted prostate cancer stem cell (PCSC) properties in vitro, including tumorsphere formation, migration, bicalutamide resistance, and decreased apoptosis. Taken together, our results indicate that SFRP1 participates in the paracrine signaling of epithelial cells, influencing them and positively regulating the stem cell phenotype through deregulation of the WNT/β-catenin pathway, which could contribute to disease progression and therapeutic failure. This research increases our molecular understanding of how CRPC progresses, which could help us find new ways to diagnose and treat the disease.

SUBMITTER: Losada-Garcia A

PROVIDER: S-EPMC10033548 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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SFRP1 induces a stem cell phenotype in prostate cancer cells.

Losada-García Alberto A Salido-Guadarrama Iván I Cortes-Ramirez Sergio Alberto SA Cruz-Burgos Marian M Morales-Pacheco Miguel M Vazquez-Santillan Karla K Rodriguez-Martinez Griselda G González-Ramírez Imelda I Gonzalez-Covarrubias Vanessa V Perez-Plascencia Carlos C Rodríguez-Dorantes Mauricio M

Frontiers in cell and developmental biology 20230309

Prostate cancer (PCa) ranks second in incidence and sixth in deaths globally. The treatment of patients with castration-resistant prostate cancer (CRPC) continues to be a significant clinical problem. Emerging evidence suggests that prostate cancer progression toward castration resistance is associated with paracrine signals from the stroma. SFRP1 is one of the extracellular proteins that modulate the WNT pathway, and it has been identified as a mediator of stromal epithelium communication. The ...[more]

PMID: 36968194

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Project description:Prostate cancer consists of secretory cells and a population of immature cells. The function of immature cells and their mutual relation with secretory cells are still poorly understood. Immature cells either have a hierarchical relation to secretory cells (stem cell model) or represent an inducible population emerging upon appropriate stimulation of differentiated cells. Hepatocyte Growth Factor (HGF) receptor c-MET is specifically expressed in immature prostate cells. Our objective is to determine the role of immature cells in prostate cancer by analysis of the HGF/c-MET pathway.Gene-expression profiling of DU145 prostate cancer cells stimulated with HGF revealed induction of a molecular signature associated with stem cells, characterized by up-regulation of CD49b, CD49f, CD44 and SOX9, and down-regulation of CD24 ('stem-like signature'). We confirmed the acquisition of a stem-like phenotype by quantitative PCR, FACS analysis and Western blotting. Further, HGF led to activation of the stem cell related Notch pathway by up-regulation of its ligands Jagged-1 and Delta-like 4. Small molecules SU11274 and PHA665752 targeting c-MET activity were both able to block the molecular and biologic effects of HGF. Knock-down of c-MET by shRNA infection resulted in significant reduction and delay of orthotopic tumour-formation in male NMRI mice. Immunohistochemical analysis in prostatectomies revealed significant enrichment of c-MET positive cells at the invasive front, and demonstrated co-expression of c-MET with stem-like markers CD49b and CD49f.In conclusion, activation of c-MET in prostate cancer cells induced a stem-like phenotype, indicating a dynamic relation between differentiated and stem-like cells in this malignancy. Its mediation of efficient tumour-formation in vivo and predominant receptor expression at the invasive front implicate that c-MET regulates tumour infiltration in surrounding tissues putatively by acquisition of a stem-like phenotype.

Project description:BackgroundMetastatic dissemination of solid tumors is often initiated by reactivation of an embryonic development program, epithelial-to-mesenchymal-transition (EMT). EMT has been associated with acquiring invasiveness and resistance to conventional therapies. However, the precise role of EMT during renal cell carcinoma is still debatable and is under investigation. In this context, our study is designed to evaluate the role of cyclosporine (CsA) and transforming growth factor-β (TGFβ) administration in inducing EMT-like state in renal carcinoma cells. We also studied the associated phenotypic changes which may lead to tumor metastasis.MethodsThe morphological changes in renal cell carcinoma cells (A498) treated with TGF-β/CsA were observed by microscopy. Atomic force microscope was used to evaluate the changes in elasticity of cells treated with TGF-β/CsA. The expression of mesenchymal and chemoresistance genes were checked by RT-PCR. Assays for migration, invasion, sphere formation ability and expression of cancer stem cell-like phenotypes were done to evaluate the metastatic potential of these cells. Lineage specific differentiations were also done to determine the acquisition of stem-cell like phenotype.ResultsOur results showed that treatment with TGF-β/CsA led to loss of epithelial characteristics and gain of mesenchymal phenotype in vitro. Changes in shape and elastic properties of the cancer cells favoured metastatic progression, increased tumorisphere formation and invasiveness post treatment. We also observed higher expression of chemoresistance and stemness markers in EMT-induced cells. These cells also differentiated to various lineages like osteoblasts, adipocytes, neural and hepatic cells when induced with the respective differentiation media.ConclusionWe concluded that TGF-β/CsA treatment led to acquisition of EMT-like cancer stem cells phenotype that enhanced local invasion and dissemination of renal carcinoma cells. This subpopulation of cells with EMT-like phenotype a can provide a better perception of the metastatic process. This can provide an in vitro system for testing pharmaceuticals for modulating EMT as a viable strategy within the therapeutic armamentarium for RCC patients. The results of our findings also suggest that CsA directly induced EMT like changes in epithelial cell which may be responsible for the potential risk of malignancy in transplant patients.

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SFRP1 induces a stem cell phenotype in prostate cancer cells.

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SFRP1 induces a stem cell phenotype in prostate cancer cells.

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