Multistage prostate carcinogenesis: the role of hormones.

M. C. Bosland, H. C. Dreef-Van Der Meulen, S. Sukumar, P. Ofner, I. Leav, X. Han, J. G. Liehr

Research output: Contribution to journalReview article

Abstract

Prostate cancer is the most frequently occurring non-skin cancer in men in the U.S.A. and other Western countries, but its etiology is poorly understood. Human prostate carcinogenesis has been viewed as a multi-step process involving progression from low histologic grade, small latent carcinoma, to large, higher grade, metastasizing carcinoma. However, recent data suggest that a variety of pathogenetic pathways exist. The precise role of hormones in the genesis of human prostate cancer remains largely undefined. It is difficult to investigate stages in the development of human prostate cancer, but some animal models provide opportunities in this regard. Short-term treatment of rats with chemical carcinogens will produce a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU). Testosterone markedly enhances prostate carcinogenesis even at doses that do not measurably increase circulating testosterone. Thus, testosterone is a strong tumor promoter for the rat prostate. All such MNU-initiated, testosterone-promoted tumors are adenocarcinomas mostly originating from the dorsolateral and anterior, but not ventral, prostate lobes. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. A variable frequency of activation of H-ras and K-ras genes occurs in human prostate carcinomas. Another rat model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. We recently found a major adduct by 32P postlabeling analysis in the tissue region that includes these ducts, but not in, e.g., the ventral prostate, of rats treated for 16-24 weeks. While it is unknown whether testosterone is a tumor promoter in this system, the presence of a DNA adduct suggests that estradiol-17 beta acts as a tumor-initiating agent in this system.

Original languageEnglish (US)
Pages (from-to)109-123
Number of pages15
JournalPrincess Takamatsu symposia
Volume22
StatePublished - 1991
Externally publishedYes

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    Bosland, M. C., Dreef-Van Der Meulen, H. C., Sukumar, S., Ofner, P., Leav, I., Han, X., & Liehr, J. G. (1991). Multistage prostate carcinogenesis: the role of hormones. Princess Takamatsu symposia, 22, 109-123.