Elevated Stromal Inflammatory Mediators Promote Prostate Cancer Progression in African American Men

Progress in prostate cancer racial disparity (PCa-HD) research has been hampered by a lack of appropriate research tools and better understanding of the tumor biology. Recent gene expression studies suggest that the tumor microenvironment (TME) may contribute to racially disparate clinical outcomes in PCa. Analysis of the prostate TME has shown increased reactive stroma associated with chronic inflammatory infiltrates in African American (AA) compared to European American (EA) patients with PCa. To better understand stromal drivers of changes in TME, we isolated prostate fibroblasts (PrF) from AA (PrF-AA) and EA (PrF-EA) PCa tissues and studied their functional characteristics. PrF-AA showed increased growth response to androgens FGF2 and PDGF. Compared to PrF-EA, conditioned media from PrF-AA significantly enhanced the proliferation and motility of PCa cell lines. Expression of markers associated with myofibroblast activation (αSMA, vimentin, and tenascin-C) were elevated in PrF-AA. In vivo tumorigenicity of an AA patient-derived prostatic epithelial cell line E006AA was significantly increased in the presence of PrF-AA compared to PrF-EA. RNA-seq data and cytokine array analysis identified a panel of potential pro-inflammatory paracrine mediators (BDNF, CHI3L1, DPPIV, FGF7, IL18BP, IL6 and VEGF) to be enriched in PrF-AA. E006AA cell lines showed increased responsiveness to BDNF ligand compared to EA-derived LNCaP and C4-2B cells. Addition of a TrkB-specific antagonist significantly reduced the pro-tumorigenic effects induced by PrF-AA compared to PrF-EA. These findings suggest that fibroblasts in the TME of AA patients may contribute to the health disparity observed in the incidence and progression of PCa tumors

https://ift.tt/2NSLZSk