Elevation of Stromal-Derived Mediators of Inflammation Promote Prostate Cancer Progression in African-American Men

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) and EA (PrF) prostate cancer tissues and studied their functional characteristics. PrF showed increased growth response to androgens FGF2 and platelet-derived growth factor. Compared with PrF, conditioned media from PrF 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 tumorigenicity of an AA patient-derived prostatic epithelial cell line E006AA was significantly increased in the presence of PrF compared with PrF, 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 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 compared with PrF 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. 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. http://cancerres.aacrjournals.org/content/canres/78/21/6134/F1.large.jpg .

DGAT1 Inhibitor Suppresses Prostate Tumor Growth and Migration by Regulating Intracellular Lipids and Non-Centrosomal MTOC Protein GM130

“…For the in vivo analysis we used sub-renal capsule grafting method. A total of 1 × 10 6 PC-3 cells were pelleted and re-suspended in 30 μl neutralized rat tail collagen prepared as described previously 54,55 . Two groups of grafts with PC-3 cells were prepared: a) Grafts with no treatment (n = 6) or b) Grafts containing DGAT1 inhibitor (33.3 μM per graft) (n = 6).…”

Prostate carcinogenesis: inflammatory storms

“…Chronic inflammation, commonly observed in pre-neoplastic and malignant prostates, is implicated as a driver of prostate carcinogenesis and progression [13][14][15][16][17][18][19] . Tumour progenitor cells of an intermediate phenotype expand in the context of inflammation to perpetuate this process 13,18,20,21 .…”

Adherence to the Mediterranean diet and grade group progression in localized prostate cancer: An active surveillance cohort

“…Although this analysis was limited by the sample size and was thus exploratory in nature; this subgroup was largely represented by African American men. Studies of tumors, 49 circulating exosomes, 50 and stromal fibroblasts 51 from African American men with PCa have demonstrated a clear role for inflammation in the development of aggressive disease within this population. In the United States, the rate of PCa diagnosis is more than 50% higher in African American men than non‐Hispanic White men, and African American men are disproportionately burdened by PCa mortality, with age‐adjusted rates 2 to 3 times higher than those of non‐Hispanic White men 9 .…”