Progress in
prostate cancer racial disparity 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
prostate cancer. Analysis of the prostate TME has shown increased reactive stroma associated with chronic inflammatory infiltrates in African-American (AA) compared with European-American (EA) patients with
prostate cancer. To better understand stromal drivers of changes in TME, we isolated prostate fibroblasts (PrF) from AA (PrF-AA) and EA (PrF-EA)
prostate cancer tissues and studied their functional characteristics. PrF-AA showed increased growth response to
androgens FGF2 and
platelet-derived growth factor. Compared with PrF-EA,
conditioned media from PrF-AA significantly enhanced the proliferation and motility of
prostate cancer cell lines. Expression of markers associated with myofibroblast activation (αSMA,
vimentin, and
tenascin-C) was 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 with PrF-EA, and
RNA-seq data and
cytokine array analysis identified a panel of potential proinflammatory 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 with EA-derived LNCaP and C4-2B cells. Addition of a TrkB-specific antagonist significantly reduced the protumorigenic effects induced by PrF-AA compared with 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
prostate cancer tumors.Significance: These findings suggest that stromal cells in the tumor microenvironment of African-American men promote progression of
prostate cancer by increasing levels of a specific set of pro-inflammatory molecules compared with European-American men.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6134/F1.large.jpg
Cancer Res; 78(21); 6134-45. ©2018 AACR.