Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue

Yuzhuo Wang, Simon W. Hayward, Anne A. Donjacour, Peter Young, Tyler Jacks, Julien Sage, Robert Cardiff, Robert D. Cardiff, Mark L. Day, Gerald R. Cunha

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6008-6017
Number of pages10
JournalCancer Research
Volume60
Issue number21
StatePublished - Nov 1 2000
Externally publishedYes

Fingerprint

Retinoblastoma
Gonadal Steroid Hormones
Prostate
Carcinogenesis
Epithelium
Mesoderm
Retinoblastoma Genes
Hyperplasia
Cadherins
Capsules
Testosterone
Estradiol
Embryonic Structures
Epithelial Cells
Carcinoma
Transplants
Kidney
Gene Knockout Techniques
Proliferating Cell Nuclear Antigen
Prostatic Hyperplasia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, Y., Hayward, S. W., Donjacour, A. A., Young, P., Jacks, T., Sage, J., ... Cunha, G. R. (2000). Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue. Cancer Research, 60(21), 6008-6017.

Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue. / Wang, Yuzhuo; Hayward, Simon W.; Donjacour, Anne A.; Young, Peter; Jacks, Tyler; Sage, Julien; Cardiff, Robert; Cardiff, Robert D.; Day, Mark L.; Cunha, Gerald R.

In: Cancer Research, Vol. 60, No. 21, 01.11.2000, p. 6008-6017.

Research output: Contribution to journalArticle

Wang, Y, Hayward, SW, Donjacour, AA, Young, P, Jacks, T, Sage, J, Cardiff, R, Cardiff, RD, Day, ML & Cunha, GR 2000, 'Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue', Cancer Research, vol. 60, no. 21, pp. 6008-6017.
Wang Y, Hayward SW, Donjacour AA, Young P, Jacks T, Sage J et al. Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue. Cancer Research. 2000 Nov 1;60(21):6008-6017.
Wang, Yuzhuo ; Hayward, Simon W. ; Donjacour, Anne A. ; Young, Peter ; Jacks, Tyler ; Sage, Julien ; Cardiff, Robert ; Cardiff, Robert D. ; Day, Mark L. ; Cunha, Gerald R. / Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue. In: Cancer Research. 2000 ; Vol. 60, No. 21. pp. 6008-6017.
@article{0b7ca5f310724b2e8a359d5b0aaef994,
title = "Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue",
abstract = "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.",
author = "Yuzhuo Wang and Hayward, {Simon W.} and Donjacour, {Anne A.} and Peter Young and Tyler Jacks and Julien Sage and Robert Cardiff and Cardiff, {Robert D.} and Day, {Mark L.} and Cunha, {Gerald R.}",
year = "2000",
month = "11",
day = "1",
language = "English (US)",
volume = "60",
pages = "6008--6017",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "21",

}

TY - JOUR

T1 - Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue

AU - Wang, Yuzhuo

AU - Hayward, Simon W.

AU - Donjacour, Anne A.

AU - Young, Peter

AU - Jacks, Tyler

AU - Sage, Julien

AU - Cardiff, Robert

AU - Cardiff, Robert D.

AU - Day, Mark L.

AU - Cunha, Gerald R.

PY - 2000/11/1

Y1 - 2000/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0034327299&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034327299&partnerID=8YFLogxK

M3 - Article

C2 - 11085521

AN - SCOPUS:0034327299

VL - 60

SP - 6008

EP - 6017

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 21

ER -