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

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.

• Authors: Kiyoshi Takahara, Howard Tearle, Mazyar Ghaffari, Martin E Gleave, Michael Pollak, Michael E Cox
• Journal: The Prostate (Prostate) Vol. 71 Issue 5 Pg. 525-37 (Apr 2011) ISSN: 1097-0045 [Electronic] United States
• PMID: 20878948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

• Androgens
• Human Growth Hormone
• Insulin-Like Growth Factor I
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases
• Prostate-Specific Antigen

Topics

• Androgens (physiology)
• Animals
• Blotting, Western
• Body Weight (physiology)
• Cell Line, Tumor
• Cell Proliferation
• Disease Models, Animal
• Enzyme Activation (physiology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Human Growth Hormone (blood, metabolism)
• Humans
• Insulin-Like Growth Factor I (analysis, metabolism)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Transplantation
• Neoplasms, Hormone-Dependent (enzymology, metabolism, pathology)
• Oncogene Protein v-akt (metabolism)
• Prostate-Specific Antigen (blood, metabolism)
• Prostatic Neoplasms (enzymology, metabolism, pathology)