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Immune Inflammation Pathways as Therapeutic Targets to Reduce Lethal Prostate Cancer in African American Men.

ABSTRACT: Despite substantial improvements in cancer survival, not all population groups have benefitted equally from this progress. For prostate cancer, men of African descent in the United States and England continue to have about double the rate of fatal disease compared to other men. Studies suggest that when there is equal access to care, survival disparities are greatly diminished. However, notable differences exist in prostate tumor biology across population groups. Ancestral factors and disparate exposures can lead to altered tumor biology, resulting in a distinct disease etiology by population group. While equal care remains the key target to improve survival, additional efforts should be made to gain comprehensive knowledge of the tumor biology in prostate cancer patients of African descent. Such an approach may identify novel intervention strategies in the era of precision medicine. A growing body of evidence shows that inflammation and the immune response may play a distinct role in prostate cancer disparities. Low-grade chronic inflammation and an inflammatory tumor microenvironment are more prevalent in African American patients and have been associated with adverse outcomes. Thus, differences in activation of immune-inflammatory pathways between African American and European American men with prostate cancer may exist. These differences may influence the response to immune therapy which is consistent with recent observations. This review will discuss mechanisms by which inflammation may contribute to the disparate outcomes experienced by African American men with prostate cancer and how these immunogenic and inflammatory vulnerabilities could be exploited to improve their survival.

SUBMITTER: Kiely M

PROVIDER: S-EPMC8227648 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared to European-American men. We tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical parameters. We also evaluated 18 non-tumor prostate tissues from 7 African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed a significant number of genes, e.g., 162 transcripts at a false-discovery rate less than 5%, to be differently expressed between African-American and European-American patients. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differently expressed genes clustering in immune response, stress response, cytokine signaling, and chemotaxis pathways. Furthermore, a two-gene tumor signature was identified that accurately differentiated between African-American and European-American patients. This finding was confirmed in a blinded analysis of a second sample set. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups. Experiment Overall Design: A total of 69 fresh-frozen prostate tumors were obtained from the NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) and the Department of Pathology at the University of Maryland (UMD). All tumors were resected adenocarcinomas that had not received any therapy prior to prostatectomy. The macro-dissected CPCTR tumor specimens (n = 59) were reviewed by a CPCTR-associated pathologist, who confirmed the presence of tumor in the specimens. These tissues were collected between 2002 and 2004 at four different sites, with each site providing tissues from both African-American and European-American patients. Information on race/ethnicity (33 African-Americans and 36 European-Americans) was either extracted from medical records (CPCTR) or obtained through an epidemiological questionnaire in which race/ethnicity was self-reported (UMD). Only one patient, a European-American, was also Hispanic. Surrounding non-tumor prostate tissue was collected from 18 of the recruited patients in this study. Of those, 7 were African-American men and 11 were European-American men. We also isolated total RNA from 10 needle biopsy specimens collected from patients at the National Naval Medical Center (one African-American and 9 European-Americans) that did not have prostate cancer. From those, we prepared two RNA pools, each representing 5 patients. Clinicopathological characteristics of the patients, including age at prostatectomy, histology, Gleason score, pathological stage, PSA at diagnosis, tumor size, extraprostatic extension, margin involvement, and seminal vesicle invasion were obtained from CPCTR. For UMD cases, this information was extracted from the medical and pathology records, if available. Written informed consent was obtained from all donors. Tissue collection and study design were approved by the institutional review boards of the participating institutions.

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Immune Inflammation Pathways as Therapeutic Targets to Reduce Lethal Prostate Cancer in African American Men.

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