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Departments of Anatomy [Y. W., A. A. D., P. Y., G. R. C.], Urology [S. W. H., R. D., G. R. C.], University of California, San Francisco, California 94143-0452; Howard Hughes Medical Institute, Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [T. J., J. S.]; University of California Davis Center for Comparative Medicine, University of California, Davis, California 95616 [R. D. C.]; and Department of Surgery, Division of Urology, University of Michigan Comprehensive Cancer Center, University of Michigan Ann Arbor, Michigan 48109 [M. L. D.]
The retinoblastoma (Rb) gene product is a prototypic tumor suppressor.
Mice lacking the Rb gene are not viable and die
in utero at 
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 atypical 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.
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