Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue

The retinoblastoma (Rb) gene product is a prototypic tumor suppressor. Mice lacking the Rb gene are not viable and die in utero at similar to 13 days of gestation. In this study, me have rescued Rb-/- prostates by grafting pe lvic organ rudiments from Rb-/- mouse embryos under the renal capsule of ad ult male nude mouse hosts. Grafts of embryonic pelvic organs developed into functional prostatic tissue. Some of the prostatic tissue generated was fu rther used to construct chimeric prostatic tissue recombinants by combining wild-type rat urogenital mesenchyme (rUGM) with Rb-/- and Rb+/+ prostatic epithelium (PRE). The tissue recombinants were grown as subcapsular renal g rafts and treated from the time of grafting with Silastic capsules containi ng 25 mg of testosterone plus 2.5 mg of estradiol, During 5-8 weeks of horm one treatment, rUGM+Rb+/+PRE, tissue recombinants developed prostatic hyper plasia, whereas PRE in rUGM(+)Rb(-/-)PRE tissue recombinants developed hype rplasia, atypical hyperplasia, and carcinoma. During carcinogenesis in rUGM +Rb-/-PRE tissue recombinants, prostatic epithelial cells of the basal line age disappeared, whereas the luminal cells underwent carcinogenesis, Epithe lial E-cadherin almost totally disappeared. In all cases, epithelial PCNA l abeling was elevated in tissue recombinants containing Rb-/- versus Rb+/+ e pithelium, These epithelial changes were associated with almost total loss of smooth muscle cells in the stroma, In contrast, in untreated hosts rUGMRb+/+PRE tissue recombinants developed normally, and rUGM+Rb-/-PRE tissue r ecombinants developed mild epithelial hyperplasia, The results of this stud y demonstrate that Rb-/- prostatic tissue can be rescued from embryonic Let hal mice and used to test its susceptibility to hormonal carcinogenesis. De letion of the Rb gene predisposes prostatic epithelium to hyperplasia and i ncreases proliferative activity. Susceptibility to hormonal carcinogenesis in response to exogenous testosterone + estradiol is manifested in the prog ression from atypical hyperplasia to carcinoma. Thus, these findings demons trate that the absence of the Rb tumor suppressor gene may predispose prost atic epithelial cells to carcinogenesis. Rescue of organs from Rb-/- embryo s not only provides an opportunity to analyze the Rb gene pathway in the de velopment and progression of prostate cancer but also provides an opportuni ty for specifically evaluating the role of the Rb pathway in development an d carcinogenesis in other organs, such as the mammary gland and colon. Beca use rUGM greatly stimulates prostatic epithelial proliferation, the tissue recombinant model is a particularly useful toot for assessing the functiona l role of other genes in prostatic carcinogenesis through use of the approp riate transgenic or gene knockout mice.