期刊
CANCER RESEARCH
卷 68, 期 9, 页码 3342-3349出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-3165
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资金
- NCI NIH HHS [R01 CA100938-04, P50 CA092131, R01 CA100938, 1R01CA100938, P50CA92131, P50 CA092131-01A10003] Funding Source: Medline
- NICHD NIH HHS [R01HD047013, R01 HD047013] Funding Source: Medline
- NIDDK NIH HHS [P30 DK063491, P30 DK063491-059002] Funding Source: Medline
The role of systemic and local insulin-like growth factor I (IGF-1) 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-1, 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 similar to 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.
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