INFLAMMATION AND ATROPHY IN PROSTATE CARCINOGENESIS

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The development of rational new strategies to prevent prostate carcinoma (CaP) relies on discovering the carcinogenic agents that target the prostate. We are exploring the hypothesis that, similar to cancers of the liver, large bowel, and stomach, prostatic carcinogenesis may be accelerated by immune-mediated oxidant stress. High grade prostatic intraepithelial neoplasia (HGPIN) is held to be the precursor to many prostatic adenocarcinomas (CaP). Proliferative inflammatory atrophy (PTA) is a common lesion occurring near inflammatory cells. We postulate that PTA maybe a precursor to HGPIN since: 1) Epithelial cells in PTA have an elevated proliferative fraction; 2) The phenotype of PTA cells is consistent with that of immature secretory cells-similar to that for cells of HGPIN and carcinoma; 3) PIA, HGPIN, and CaP all occur with high prevalence in the peripheral zone, and with low prevalence in the central zone of the human prostate; 4) PTA and HOPIN occur in close proximity, with frequent morphological transitions between them. We address the hypothesis that PTA leads to HGPIN/CaP by designing experiments to answer the following questions: 1) Is there a greater extent of PTA in cases containing HGPTN/CaP as compared to controls without HGPIN/CaP? 2) Do the differences in incidence of CaP between South East Asians and North Americans relate to differences in the amounts of PTA? 3) Are there similar molecular genetic alterations on the short arm of chromosome 8 in PIA as is known for HGPIN and CaP? 4) Are there similar gains of genetic material from chromosome 8q and other chromosomes in PTA as, again, is known in HGPIN and CaP? 5) Can spontaneous and induced HGPIN and CaP in the rat prostate be prevented by inhibiting the host inflammatory response? If the results of these studies implicate the host inflammatory response and PIA in prostatic carcinogenesis, then rational trials for prostate cancer chemoprevention could be devised based on anti-inflammatory agents, and PTA be a new biomarker for assessing prostate cancer risk. Finally, new emphasis would be focused on finding the cause of chronic inflammation in the prostate with an aim towards its eradication.