Targeted deletion of hepatic Igf1 in TRAMP mice leads to dramatic alterations in the circulating insulin-like growth factor axis but does not reduce tumor progression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008-05, Vol.68 (9), p.3342-3349
• Main Authors: Anzo, Makoto, Cobb, Laura J, Hwang, David L, Mehta, Hemal, Said, Jonathan W, Yakar, Shoshana, LeRoith, Derek, Cohen, Pinchas
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - blood; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animals; Disease Progression; Female; Gene Deletion; Genotype; Growth Hormone - blood; Insulin-Like Growth Factor Binding Protein 2 - blood; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-Like Growth Factor I - analysis; Insulin-Like Growth Factor I - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutagenesis, Site-Directed; Neoplasm Metastasis; Prostatic Neoplasms - blood; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Serum - chemistry; Signal Transduction - genetics; Tumor Burden
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-3165

The role of systemic and local insulin-like growth factor I (IGF-I) in the development of prostate cancer is still controversial. Transgenic adenocarcinoma mouse prostate (TRAMP) mice express the SV40 T-antigen under the control of the probasin promoter, and spontaneously develop prostate cancer. We crossed TRAMP mice with liver IGF-deficient (LID) mice to produce LID-TRAMP mice, a mouse model of prostate cancer with low serum IGF-I, to allow us to study the effect of circulatory IGF-I levels on the development of prostate cancer. LID mice have a targeted deletion of the hepatic Igf1 gene but retain normal expression of Igf1 in extrahepatic tissues. Serum IGF-I and IGFBP-3 levels in LID and LID-TRAMP mice were measured using novel assays, which showed that they are approximately 10% and 60% of control L/L- mice, respectively. Serum growth hormone (GH) levels of LID-TRAMP mice were 3.5-fold elevated relative to L/L-TRAMP mice (P < 0.001), but IGFBP-2 levels were not different. Surprisingly, rates of survival, metastasis, and the ratio of genitourinary tissue weight to body weight were not significantly different between LID-TRAMP and L/L-TRAMP mice. There was also no difference in the pathologic stage of the prostate cancer between the two groups at 9 to 19 weeks of age. LID-TRAMP tumors displayed increased levels of GH receptors and increased Akt phosphorylation. These results are in striking contrast with the published model of the GH-deficient lit/lit-TRAMP, which has smaller tumors and improved survival, and indicate that the reduction in systemic IGF-I is not sufficient to inhibit prostate cancer tumor progression in the TRAMP model, which may require a reduction of GH levels as well.