Abstract A78: The role of tumor microenvironment in prostate cancer of African Americans

Abstract

Abstract Background: The incidence of prostate cancer (PCa) is approximately 60% higher and the mortality rate 2 to 3 times greater among African American men (AA) in the U.S. compared to men with a European background, European Americans (EA). Men of West African ancestry from the Caribbean and South America share a similar increase in incidence and mortality to AA suggesting a genetic contribution to these outcomes. We have observed that expression of hundreds of genes in the tumor microenvironment is strikingly different for AA and EA patients1. The majority of significant differences in the stroma of AA patients were down-regulated compared to EA patients. These expression alterations could be related to somatically acquired DNA changes in the stroma but non-tumor tissue in cancer usually exhibits far fewer genetic changes than tumors. Thus, it may be that inherited or distinct environmental changes are responsible for the differences seen between AA and EA stroma. Whatever the basis of the large number of differences observed, the distinct patterns for AA and EA argue strongly, and for the first time, that there are many molecular distinctions between PCa in these races that are resident in the tumor-adjacent microenvironment. We hypothesize that the stroma of AA PCa exhibits a large-scale lower expression of protein mediators of cellular antitumor immunity and reduction in factors involved in cell-cell and cell-extracellular matrix (ECM) contacts. Such differences may, thereby, favor aggressive cancer including early metastases in AA. Methods: In order to test the basis of the relative decreased expression in AA stroma, ChIP methods for isolating methylated and unmethylated DNA combined with NGS have been used to define methylated sites in two PCa EA cells lines as well as FFPE samples of stroma from EA and AA PCa. To validate the microarray data, we are using Tumor Microarrays from both CA (n=443) and AA (n=105) patients to confirm in immunohistochemistry (IHC) the differential protein expression of many immune and ECM mediators identified in our initial studies. Results: We validated the ChIP-NGS methods by quantitatively confirming significant methylation within the promoter regions of LnCAP and DU135 cells compared to immortalized normal p69 cells for 35 reported methylated genes including GSTPi. Of the 965 largest down-regulated transcripts observed in AA stroma (1), 237 were observed to exhibit increased promoter methylation in AA stroma tissue compared to EA stroma. These 237 genes identified four main pathways (WNT, TGFβ, integrin mediated cell matrix adhesion, and EMT, all with p<0.00001) that are deregulated in AA stroma compared to CA stroma. The IHC studies have shown that CD8+ cell infiltration is significantly greater into the tumors of EA patients than those from AA. Immune mediators of antigen presentation are greater expressed in EA tumors, strongly suggesting immune processes involved in anti-tumor immunity may be more efficient in EA than AA patients. In addition, factors mediating interaction with the ECM such as ITGA5 and ECM formation such as COL4α1 also are increased in EA. Conclusions: These preliminary studies support the hypothesis that the stroma of AA PCa exhibits a large-scale lower expression of protein mediators of cellular antitumor immunity and reduction in factors involved in cell-cell and cell-ECM contacts. The results suggest a role for the microenvironment in the aggressive features of PCa of AA. Acknowledgements: This study was funded by the NCI Comprehensive Partnerships to Reduce Cancer Health Disparities (CPRCHD) grants (U54CA132384 and U54CA132379) and by 1U01CA162147 (KLM), NCI 3UL1TR000004-07S2 (DAM) and NCI UO1CA152738A, P30CA62203 and the Congressionally Directed Medical Research Programs W81XWH-12-PCRP-IDA (DAM, MMCC). 1. Kinseth M, A., Z. Jia, et al., 2014. Int. J. Cancer 134: 81-91. DOI: 10.1002/ijc.28326. Citation Format: Farah Rahmatpanah, Tracy Luu, Pardis Zaeri, Xin Chen, Yuanjie Hu, Joe Adams, Harmony Saunders, Sam Takahashi, Michael McClelland, Kathleen L. McGuire, Dan Mercola. The role of tumor microenvironment in prostate cancer of African Americans. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A78.