Borowsky Alexander D, Dingley Karen H, Ubick Esther, Turteltaub Kenneth W, Cardiff Robert D, Devere-White Ralph
University of California and the Lawrence Livermore NationalLaboratory, USA.
Neoplasia. 2006 Sep;8(9):708-15. doi: 10.1593/neo.06373.
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) has been implicated as a major mutagenic heterocyclic amine in the human diet and is carcinogenic in the rat prostate. To validate PhIP-induced rat prostatic neoplasia as a model of human prostate cancer progression, we sought to study the earliest histologic and morphologic changes in the prostate and to follow progressive changes over time. We fed sixty-seven 5-week-old male Fischer F344 rats with PhIP (400 ppm) or control diets for 20 weeks, and then sacrificed animals for histomorphologic examination at the ages of 25, 45, and 65 weeks. Animals treated with PhIP showed significantly more inflammation (P = .002, > .001, and .016 for 25, 45, and 65 weeks, respectively) and atrophy (P = .003, > .001, and .006 for 25, 45, and 65 weeks, respectively) in their prostate glands relative to controls. Prostatic intraepithelial neoplasia (PIN) occurred only in PhIP-treated rats. PIN lesions arose in areas of glandular atrophy, most often in the ventral prostate. Atypical cells in areas of atrophy show loss of glutathione S-transferase pi immunostaining preceding the development of PIN. None of the animals in this study developed invasive carcinomas, differing from those in previous reports. Overall, these findings suggest that the pathogenesis of prostatic neoplasia in the PhIP-treated rat prostate proceeds from inflammation to postinflammatory proliferative atrophy to PIN.
2-氨基-1-甲基-6-苯基咪唑并(4,5-b)吡啶（PhIP）被认为是人类饮食中一种主要的致突变杂环胺，并且在大鼠前列腺中具有致癌性。为了验证PhIP诱导的大鼠前列腺肿瘤作为人类前列腺癌进展模型的有效性，我们试图研究前列腺最早的组织学和形态学变化，并随时间追踪其渐进性变化。我们给67只5周龄的雄性Fischer F344大鼠喂食含PhIP（400 ppm）的饲料或对照饲料20周，然后在25、45和65周龄时处死动物进行组织形态学检查。与对照组相比，接受PhIP处理的动物前列腺中炎症（25周、45周和65周时P值分别为0.002、>0.001和0.016）和萎缩（25周、45周和65周时P值分别为0.003、>0.001和0.006）明显更多。前列腺上皮内瘤变（PIN）仅发生在接受PhIP处理的大鼠中。PIN病变出现在腺体萎缩区域，最常见于腹侧前列腺。萎缩区域的非典型细胞在PIN发生之前显示谷胱甘肽S-转移酶pi免疫染色缺失。本研究中没有动物发生浸润性癌，这与之前的报道不同。总体而言，这些发现表明，PhIP处理的大鼠前列腺中肿瘤形成的发病机制是从炎症发展到炎症后增殖性萎缩再到PIN。
