Bosland M C
Institute of Environmental Medicine, New York University Medical Center, Tuxedo 10987.
J Cell Biochem Suppl. 1992;16H:89-98. doi: 10.1002/jcb.240501221.
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 may exist. The precise etiology and pathogenesis of human prostate cancer remain 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 produces a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. Chronic treatment with testosterone also produces a low prostate carcinoma incidence. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU) and 3,2'-dimethyl-4-aminobiphenyl (DMAB). 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- or DMAB-initiated and/or testosterone-promoted tumors are adenocarcinomas; most originate from the dorsolateral and anterior, but not ventral, prostate lobes. These tumors share a number of important characteristics with human prostate cancer. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. Another high incidence prostate carcinogenesis model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta to rats in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. While it is unknown whether testosterone is a tumor promoter in this system, preliminary studies indicate the formation of a DNA adduct in the target tissue, which suggests that estradiol-17 beta acts as a tumor initiating agent in this system. The high incidence models mentioned earlier are adequate for the study of chemoprevention of prostatic carcinogenesis. Analysis of shifts in the relative incidence of metastasizing carcinoma, grossly apparent but not-metastasizing carcinoma, microscopic-size carcinoma, and carcinoma in situ or atypical hyperplasia may allow study of the modifying effects of potential chemopreventive agents on tumor progression in these animal models of prostatic carcinogenesis.
人类前列腺癌的发生被视为一个多步骤过程，包括从低组织学分级、小的潜伏癌发展为大的、高分级的转移性癌。然而，最近的数据表明可能存在多种致病途径。人类前列腺癌的确切病因和发病机制在很大程度上仍不明确。研究人类前列腺癌的发展阶段很困难，但一些动物模型在这方面提供了机会。用化学致癌物对大鼠进行短期治疗会产生低发病率（5 - 15%）的前列腺癌，前提是在致癌物暴露期间前列腺细胞增殖增强。用睾酮进行慢性治疗也会产生低前列腺癌发病率。只有在给予致癌物如N - 甲基 - N - 亚硝基脲（MNU）和3,2'-二甲基 - 4 - 氨基联苯（DMAB）后用睾酮进行慢性治疗，才能产生高发病率的癌症。即使在剂量未显著增加循环睾酮的情况下，睾酮也能显著增强前列腺癌的发生。因此，睾酮是大鼠前列腺的一种强肿瘤促进剂。所有这些由MNU或DMAB引发和/或由睾酮促进的肿瘤都是腺癌；大多数起源于背外侧和前部前列腺叶，而非腹侧前列腺叶。这些肿瘤与人类前列腺癌有许多重要特征相同。在这些癌中，K - ras基因通过G35到A突变激活的频率很高（70%）。另一种高发病率的前列腺癌发生模型代表了不同的致病途径，则涉及给大鼠长期联合低剂量睾酮给予17β - 雌二醇。由此产生的癌是低分级的，并且仅起源于背外侧和前部前列腺的尿道周围导管。虽然尚不清楚睾酮在这个系统中是否是肿瘤促进剂，但初步研究表明在靶组织中形成了DNA加合物，这表明17β - 雌二醇在这个系统中作为肿瘤起始剂起作用。前面提到的高发病率模型足以用于前列腺癌化学预防的研究。分析转移性癌、肉眼明显但未转移的癌、微小尺寸癌以及原位癌或非典型增生的相对发病率变化，可能有助于研究潜在化学预防剂对这些前列腺癌发生动物模型中肿瘤进展的调节作用。
