The influence of growth hormone/insulin-like growth factor deficiency on prostatic dysplasia in pbARR2-Cre, PTEN knockout mice

作者：Takahara K; Ibuki N; Ghaffari M; Tearle H; Ong C J; Azuma H; Gleave M E; Pollak M; Cox M E^*

来源：Prostate Cancer and Prostatic Diseases, 2013, 16(3): 239-247.

DOI：10.1038/pcan.2013.14

• prostatic intraepithelial neoplasia
• transgenic mouse
• endocrine hormone
• phosphatase tensin homolog
• growth hormone receptor hormone

BACKGROUND: Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth.
METHODS: The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (Jit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN +/+) mice. How suppressed GH/IGF-I levels impacted growth of PTEN -/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum.
RESULTS: Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN -/- littermates. While the anterior lobes of lit/+ PTEN -/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20-week-old lit/lit and lit/+ PTEN -/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N-cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH.
CONCLUSIONS: These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed.

• 出版日期2013-9