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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

¹ David Geffen School of Medicine at UCLA, Los Angeles, California and ² Mount Sinai School of Medicine, New York, New York

Requests for reprints: Pinchas Cohen, Pediatric Endocrinology, University of California at Los Angeles, 10833 Le Conte Avenue, 22-315 MDCC, Los Angeles, CA 90095. Phone: 310-206-5844; E-mail: hassy{at}mednet.ucla.edu.

Key Words: Prostate cancer • TRAMP • IGF-I • LID mice • Growth hormone

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 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. [Cancer Res 2008;68(9):3342–9]