ZIA BC 010624 (ZIA) | |||
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Title | The Molecular Profile of Prostate Tumors in African-American Men | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Ambs, Stefan | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $207,533 | Project Dates | 10/01/2003 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Interferon (30.0%) |
Prostate (100.0%) | ||
Research Type | |||
Cancer Progression and Metastasis Endogenous Factors in the Origin and Cause of Cancer |
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Abstract | |||
Previously, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. Analyzing the resulting datasets, we identified gene expression differences between African-American and European-American patients that portray the existence of a distinct tumor microenvironment for these two patient groups. Many of the differently expressed genes were immune-regulatory. Perhaps most significant was the presence of a distinct interferon signature in many of the African-American tumors. As now discovered by us, this signature is almost identical with an interferon-related DNA damage resistance signature (IRDS) that predicts resistance to chemotherapy and radiation. The presence of IRDS in African-American tumors may not only affect the response of them to immune-based therapies but may also make them more resistant to standard therapy including radiation therapy. In addition, IRDS has been linked to the pro-metastatic epithelial to mesenchymal transition of cancer cells and is induced by interactions between fibroblasts and tumor cells. Thus, IRDS may also promote the metastatic process. We completed very recently the analysis of two independent datasets with gene expression profiles from African-American and European-American tumors, which showed that IRDS is significantly more common in tumors from the African-American patients than in tumors from European-American patients in both datasets. To explore the origin of IRDS, we interrogated the expression profiles of isolated primary human prostate epithelial cells from 14 African-American patients and 13 European-American patients for the presence of IRDS. This analysis led to the finding that IRDS is present in these cultured cells, thus persisting in cancer cells after being removed from the tumor microenvironment, and was observed in 5 out of 14 (36%) isolates from African-American patients versus 2 out of 13 (15%) isolates from European-American patients. We believe that the heightened prevalence of IRDS in cancer cells from African-American patients could be clinically very significant and warrants further investigations into the origin of this signature, and also how this signature can be targeted. To further understand the possible origin of the detected immunobiological differences in tumors of African-American and European-American prostate cancer patients, we started with the evaluation of blood-based immune cell profiles of African-American and European-American prostate cancer patients and age-matched population-based controls with a focus of subpopulation that have immune-regulatory functions in cancer biology. It was the hypothesis of this project that immune cell subpopulation that have immune-regulatory functions in cancer biology are different in abundance in these two population groups. This project has been completed in FY13. We did not observe that any of the investigated immune cell subpopulations (myeloid-derived suppressor cells, T- and B-cell-derived suppressor cells, dendritic cell subpopulations and polarized macrophages) was different in abundance comparing the blood samples from African-American and European-American prostate cancer patients. Currently we are investigating whether the development of this signature could be functionally linked to a germline variation that frequently occurs in men of African ancestry but is rather uncommon in men of European ancestry and encodes a novel interferon termed interferon lambda 4. The presence of an interferon gene signature in prostate tumors suggests a possible involvement of either a viral infection in disease pathology or the reactivation of endogenous retroviruses in the tumor microenvironment. This hypothesis was further supported by our finding that the interferon signature in prostate tumors coincides with a gene signature of retroviral activation. Thus, we started a project exploring the presence of viral infections and the reactivation of" |