Abstract
Introduction: Prostate cancer (PCa) is the third leading cause of cancer death in American men. African American (AA) men are more likely to be diagnosed with advanced prostate cancer and are 2-3 times more likely to die from the disease than Caucasian American (CA) men. Chronic inflammation is implicated as a major risk factor for PCa, and genes involved in inflammatory pathways are reported as more prevalent in tumors from AA men versus CA men. Specifically, interleukin-1β (IL-1β), IL-6, IL-8, and IL-10 have consistently been identified as overexpressed in the tumor microenvironment of AA men. These interleukins are in involved in the attraction, activation, or maintenance of innate immune cells such as neutrophils and macrophages. However, it is not well understood where these interleukins are expressed in the prostate and by what cell types they produced. We aim to address these specific questions using a novel in situ hybridization technique. Uncovering the inflammatory topography of PCa may contribute to our understanding of chronic inflammation in tumor development and progression, particularly among AA men.
Methods: The expression pattern and cellular localization of IL-1β, IL-6, IL-8, and IL-10 were evaluated using a highly specific RNA in situ hybridization assay (RNAscope) to analyze formalin-fixed, paraffin-embedded tissues of low-grade (Gleason ≤ 3+4) and higher-grade (Gleason ≥ 4+3) PCa from AA and CA men. Immunohistochemical analysis of neutrophils (CD66ce) and macrophages (CD68) was used to assess the expression pattern of these immune cells within the same cohort.
Results: Limited IL-1β and IL-10 expression was observed across all samples. Consistent with our previous reports in CA men, IL-6 mRNA is not expressed in tumor cells and is largely confined to the stromal compartment. IL-6 expression was predominantly in endothelial cells and to a lesser extent in atrophic epithelial cells of both AA and CA men. IL-6 is also highly expressed in stromal cells in areas of acute inflammation. IL-8 was the most abundantly detected cytokine within our cohort. In benign regions, IL-8 expression was predominantly observed in epithelial cells in regions of prostatic atrophy. IL-8 expression was also apparent in multiple tumors, both in tumor cells and infiltrating immune cells. We also observed marked IL-8 expression in urothelial cells in a subset of cases. Interestingly, tumor-infiltrating neutrophils and a marked increase in tumor-infiltrating macrophages were observed within tumors in a subset of cases.
Conclusions: There is differential expression of cytokines among men with PCa. Our future studies aim to determine whether our results could help to explain the disparate burden of advanced PCa among AA men.
Citation Format: Janielle P. Maynard, Angelo M. De Marzo, Karen S. Sfanos. The inflammatory microenvironment in prostate cancer racial disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B54.
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