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 approximately 13 days of gestation. In this study, we have rescued Rb-/- prostates by grafting pelvic organ rudiments from Rb-/- mouse embryos under the renal capsule of adult male nude mouse hosts. Grafts of embryonic pelvic organs developed into functional prostatic tissue. Some of the prostatic tissue generated was further 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 grafts and treated from the time of grafting with Silastic capsules containing 25 mg of testosterone plus 2.5 mg of estradiol. During 5-8 weeks of hormone treatment, rUGM+Rb+/+PRE tissue recombinants developed prostatic hyperplasia, whereas PRE in rUGM+Rb-/-PRE tissue recombinants developed hyperplasia, atypical hyperplasia, and carcinoma. During carcinogenesis in rUGM+Rb-/-PRE tissue recombinants, prostatic epithelial cells of the basal lineage disappeared, whereas the luminal cells underwent carcinogenesis. Epithelial E-cadherin almost totally disappeared. In all cases, epithelial PCNA labeling was elevated in tissue recombinants containing Rb-/- versus Rb+/+ epithelium. These epithelial changes were associated with almost total loss of smooth muscle cells in the stroma. In contrast, in untreated hosts rUGM+Rb+/+PRE tissue recombinants developed normally, and rUGM+Rb-/-PRE tissue recombinants developed mild epithelial hyperplasia. The results of this study demonstrate that Rb-/- prostatic tissue can be rescued from embryonic lethal mice and used to test its susceptibility to hormonal carcinogenesis. Deletion of the Rb gene predisposes prostatic epithelium to hyperplasia and increases proliferative activity Susceptibility to hormonal carcinogenesis in response to exogenous testosterone + estradiol is manifested in the progression from atypica hyperplasia to carcinoma. Thus, these findings demonstrate that the absence of the Rb tumor suppressor gene may predispose prostatic epithelial cells to carcinogenesis. Rescue of organs from Rb-/- embryos not only provides an opportunity to analyze the Rb gene pathway in the development and progression of prostate cancer but also provides an opportunity for specifically evaluating the role of the Rb pathway in development and carcinogenesis in other organs, such as the mammary gland and colon. Because rUGM greatly stimulates prostatic epithelial proliferation, the tissue recombinant model is a particularly useful tool for assessing the functional role of other genes in prostatic carcinogenesis through use of the appropriate transgenic or gene knockout mice.
Wang
Y
Y
Department of Anatomy, University of California, San Francisco 94143-0452, USA.
Hayward
S W
SW
Donjacour
A A
AA
Young
P
P
Jacks
T
T
Sage
J
J
Dahiya
R
R
Cardiff
R D
RD
Day
M L
ML
Cunha
G R
GR
D000818:Animals; D003043:Cocarcinogenesis; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000633:toxicity*; D005260:Female; D016161:Genes, Retinoblastoma / Q000502:physiology; D012739:Gonadal Steroid Hormones / Q000633:toxicity*; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D011247:Pregnancy; D011470:Prostatic Hyperplasia / Q000139:chemically induced / Q000235:genetics; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D013370:Subrenal Capsule Assay; D013739:Testosterone / Q000633:toxicity*
D012739:Gonadal Steroid Hormones; D016160:Retinoblastoma Protein; D013739:Testosterone; D004958:Estradiol