Abstract
Chronic inflammation and African ancestry are implicated in prostate cancer aggressiveness, and inflammation-related genes are more highly expressed in prostate cancer in African American men. IL8 secretion is also implicated in prostate cancer progression and castration resistance. We used RNA in situ hybridization to localize IL1β, IL6, IL8, and IL10 mRNA in low- and high-grade prostate cancer from African American and European American men. IL8 was the most abundantly expressed and the only interleukin detected in tumor cells. We further interrogated IL8 expression in primary and metastatic prostate cancer tissue microarrays and both androgen-dependent and castration-resistant patient-derived xenografts (PDX). IL8 was significantly increased in both tumor and benign regions of higher grade cases (ISUP Grade Group 4-5), but there was no difference between races. We determined that IL8 expression in prostate cancer cell lines, distant metastases, and PDX lines was associated with androgen receptor (AR) loss, but not castration resistance. Reciprocal IL8 and AR expression was also observed in high IL8-expressing atrophy lesions with simultaneous AR downregulation. Finally, we show that IL8 is likely repressed by AR binding to the IL8 promoter and is inducible in prostate cancer cells stimulated with lipopolysaccharide only in cells with AR loss. Likewise, AR knockdown in androgen-dependent cells induced IL8 expression, further demonstrating that AR represses IL8 expression. In conclusion, IL8 expression in the tumor microenvironment is associated with aggressive prostate cancer and with AR loss in metastatic disease. IMPLICATIONS: IL8 expression is repressed by AR and is associated with prostate cancer aggressiveness and AR loss in metastatic disease.
Highlights
Prostate cancer is the second leading cause of cancer-related deaths in American men, and African American (AA) men are two to three times more likely to die from prostate cancer than European American (EA) men [1, 2]
Tissue microarray (TMA) sets were constructed from (i) lower grade and higher grade primary prostate cancer tissues obtained from prostatectomy specimens from 60 AA and 60 EA men matched for patient age (Æ3 years), tumor grade, and stage and contained four tissue spots of the index tumor from each case as well as four benign tissue spots taken from a block containing only benign tissue, with deliberate avoidance of areas with overt inflammation, and (ii) 26 autopsy metastatic tissue samples from 2 AA and 4 EA men
We conducted RNA in situ hybridization (RISH) on whole tissue sections from a representative tumor-containing block and a matched benign tissue block from 19 EA and 19 AA patients (n 1⁄4 38 patients, Supplementary Table S1) to determine the cellular localization and distribution of IL1b, IL6, IL8, and IL10
Summary
Prostate cancer is the second leading cause of cancer-related deaths in American men, and African American (AA) men are two to three times more likely to die from prostate cancer than European American (EA) men [1, 2]. Some studies indicate that disparities in access to quality care contribute to these differences in prostate cancer outcomes among races, whereas others identify genomic alterations and factors in the tumor microenvironment (TME), such as increased inflammation, in AA men that may promote prostate cancer aggressiveness [3,4,5,6]. Prostate cancer development may be mediated by environmental exposures that contribute to chronic inflammation—which is fre-. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Kulac: Department of Pathology, Koc University School of Medicine, Istanbul, Turkey; and current address for J.A. Baena-Del Valle, Department of Pathology and Laboratory Medicine, Fundacion Santa Fe de Bogota University Hospital, Bogota, Colombia
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