Human prostate cancer xenografts in lit/lit mice exhibit reduced growth and androgen-independent progression

Kiyoshi Takahara, Howard Tearle, Mazyar Ghaffari, Martin E. Gleave, Michael Pollak, Michael E. Cox

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background The growth hormone/insulin-like growth factor I (GH/IGF-I) axis has been linked to prostate cancer (PCa) risk. Although previous studies indicate that human breast cancers and a murine PCa model develop more slowly in murine hosts homozygous for a missense mutation in the GH-releasing hormone receptor (lit/lit) whose "little" dwarfed phenotype is caused by suppressed GH and IGF-I production, the role of these two hormones remains controversial. Methods To assess how the GH/IGF-I axis influences androgen-responsive, castration-resistant (CR), and androgen-independent (AI) growth of human PCa, we compared xenograft growth of the androgen-responsive human PCa cells, LNCaP, and AI human PCa cells, PC3, in intact and castrate Nod/SCID lit/lit and lit/+ mice, and in vitro growth of these cell lines in lit/lit and lit/+ serum-containing media supplemented with GH or IGF-I. Results Tumor growth and PSA accumulation rates were suppressed in LNCaP tumor-bearing lit/lit mice pre- and post-castration. Growth of PC3 xenografts in lit/lit mice was also suppressed. In vitro proliferation of LNCaP and PC3 cells cultured in media containing lit/lit mouse serum was decreased as compared to growth in media containing lit/+ serum. Suppressed growth in lit/lit serum could be restored by the addition of IGF-I, and to a lesser extent, GH. Differences in growth correlated with differences in steady-state AKT and ERK1/2 activation. ConclusionS This study demonstrates that circulating GH and IGF-I can promote androgen-responsive growth, CR progression, and AI expansion of PTEN-deficient human PCa cell xenografts and indicates that IGF-I can promote PCa growth in a suppressed GH environment. Prostate 77:525-537, 2011.

Original languageEnglish
Pages (from-to)525-537
Number of pages13
JournalProstate
Volume71
Issue number5
DOIs
Publication statusPublished - 01-04-2011
Externally publishedYes

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Heterografts
Androgens
Prostatic Neoplasms
Insulin-Like Growth Factor I
Growth
Castration
Serum
Growth Hormone
Hormones
Missense Mutation
Prostate
Cultured Cells
Neoplasms
Breast Neoplasms
Phenotype
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

Cite this

Takahara, Kiyoshi ; Tearle, Howard ; Ghaffari, Mazyar ; Gleave, Martin E. ; Pollak, Michael ; Cox, Michael E. / Human prostate cancer xenografts in lit/lit mice exhibit reduced growth and androgen-independent progression. In: Prostate. 2011 ; Vol. 71, No. 5. pp. 525-537.
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Human prostate cancer xenografts in lit/lit mice exhibit reduced growth and androgen-independent progression. / Takahara, Kiyoshi; Tearle, Howard; Ghaffari, Mazyar; Gleave, Martin E.; Pollak, Michael; Cox, Michael E.

In: Prostate, Vol. 71, No. 5, 01.04.2011, p. 525-537.

Research output: Contribution to journalArticle

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AU - Cox, Michael E.

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AB - Background The growth hormone/insulin-like growth factor I (GH/IGF-I) axis has been linked to prostate cancer (PCa) risk. Although previous studies indicate that human breast cancers and a murine PCa model develop more slowly in murine hosts homozygous for a missense mutation in the GH-releasing hormone receptor (lit/lit) whose "little" dwarfed phenotype is caused by suppressed GH and IGF-I production, the role of these two hormones remains controversial. Methods To assess how the GH/IGF-I axis influences androgen-responsive, castration-resistant (CR), and androgen-independent (AI) growth of human PCa, we compared xenograft growth of the androgen-responsive human PCa cells, LNCaP, and AI human PCa cells, PC3, in intact and castrate Nod/SCID lit/lit and lit/+ mice, and in vitro growth of these cell lines in lit/lit and lit/+ serum-containing media supplemented with GH or IGF-I. Results Tumor growth and PSA accumulation rates were suppressed in LNCaP tumor-bearing lit/lit mice pre- and post-castration. Growth of PC3 xenografts in lit/lit mice was also suppressed. In vitro proliferation of LNCaP and PC3 cells cultured in media containing lit/lit mouse serum was decreased as compared to growth in media containing lit/+ serum. Suppressed growth in lit/lit serum could be restored by the addition of IGF-I, and to a lesser extent, GH. Differences in growth correlated with differences in steady-state AKT and ERK1/2 activation. ConclusionS This study demonstrates that circulating GH and IGF-I can promote androgen-responsive growth, CR progression, and AI expansion of PTEN-deficient human PCa cell xenografts and indicates that IGF-I can promote PCa growth in a suppressed GH environment. Prostate 77:525-537, 2011.

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