Abstract
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.
Highlights
Despite advances in the last 20 years in the diagnosis and treatment of prostate cancer, the incidence and death rate is still significantly higher for African Americans (AA) compared with European-American (EA) men [1]
Addition of a TrkB-specific antagonist significantly. 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
We show that among the proinflammatory factors secreted by PrFÀAA, paracrine activation of TrkB signaling by stromal-derived brain-derived neutrophic factor (BDNF) can increase the tumorigenicity of prostate cancer cells and potentially the progression of tumors in AA patients with prostate cancer
Summary
Despite advances in the last 20 years in the diagnosis and treatment of prostate cancer, the incidence and death rate is still significantly higher for African Americans (AA) compared with European-American (EA) men [1]. Socioeconomic factors may be responsible to a certain extent, it is appreciated that intrinsic differences in genetics and tumor biology make AA men more prone to aggressive prostate cancer. Tumor evolution (from local carcinogenesis to distant metastasis) is strongly influenced by the microenvironmental conditions encountered by cancer cells. The microenvironment is viewed as a part of the extended phenotype of tumors that influences the proliferation and migration of cancer cells. The tumor microenvironment (TME) is rich in cellular (inflammatory and immune cells, fibroblasts, endothelial cells, nerves, and others) and noncellular elements (enzymes, growth factors, matrix elements) providing a framework that can modulate cancer cell phenotype. Myofibroblasts, or activated fibroblasts expressing a-smooth muscle actin (aSMA) together with nonmyofibroblasts cells present in the TME make the core of the CAF population [5]. CAF are known drivers of tumor progression, exerting their effects via paracrine and juxtacrine mechanisms [6]
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