Abstract 5068: Distinct pro-inflammatory cytokines in prostate fibroblasts from African-Americans with prostate cancer increase the tumorigenicity of cancer cells

Abstract

Abstract Introduction: African-American (AA) men are disproportionately affected by prostate cancer (PCa) compared with Caucasian (CA) men. AA men have higher PCa incidence and, once diagnosed, a higher stage-specific mortality rate (2.4 times higher) than CA men. Although socioeconomic factors partially explain such differences, a growing body of new scientific evidence suggests that biological factors, such as differences at the genetic and molecular level could be more critical than previously thought for the observed racial PCa disparities in incidence and outcome. Recent gene expression studies revealed that differences in the tumor microenvironment (TME) of AA vs. CA prostate tumors could affect the immune-inflammatory milieu. Fibroblasts are important regulators of stromal-epithelial paracrine interactions (SEI) in the TME. We isolated fibroblasts from AA and CA PCa patients and compared their biological effects in vitro and in vivo on PCa cell lines. Methods: Prostate fibroblasts were isolated from AA (PrF-AA) and CA (PrF-CA) patient tissues. Characterization of PrF included assaying their proliferation and expression of potential markers associated with the activation of carcinoma associated fibroblasts. In vitro effects of AA vs. CA fibroblasts on PCa cell proliferation and motility were studied. In vivo, the pro-tumorigenic properties of fibroblasts were tested using a subrenal xenograft model in SCID mice. RNA-Seq and cytokine array analysis of potential paracrine mediators of tumorigenesis was performed. Immunohistochemical analysis of a panel of putative stromal markers associated with racial differences was assessed in a cohort of PCa tissues from AA and CA. Results: Prostate fibroblasts from AA vs. CA men exhibit increased proliferation in response to known stromal mitogens. Expression of markers associated with myofibroblast activation (αSMA, vimentin and Tenascin-C) were significantly elevated in AA. Interestingly, expression of the androgen receptor (AR) and activation of AR signaling was significantly increased in PrF-AA compared to PrF-CA. The paracrine effects of PrF-AA on PCa cell proliferation and motility were significantly greater compared to those induced by PrF-CA. In an in vivo model, PRF-AA induced formation of larger and more invasive tumors by the AA PCa cell line E006AA compared to PRF-CA. Analysis of downstream regulatory pathways and potential paracrine mediators identified a panel of pro-inflammatory cytokines notably interleukins (IL6, IL11, IL17, IL18BP), growth factors (VEGF, FGF, BDNF), and other mediators enriched in PRF-AA. Conclusions: Prostate fibroblasts from African American men show enhanced secretion of pro-inflammatory and pro-proliferative mediators that can potentially increase the tumorigenicity of PCa cells through selective paracrine mechanisms. Citation Format: Marc Gillard, Alejandro Morales, Susan Crawford, Charles Brendler, Donald Vander Griend, Omar Franco. Distinct pro-inflammatory cytokines in prostate fibroblasts from African-Americans with prostate cancer increase the tumorigenicity of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5068.