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.
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.
Anzo
Makoto
M
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Cobb
Laura J
LJ
Hwang
David L
DL
Mehta
Hemal
H
Said
Jonathan W
JW
Yakar
Shoshana
S
LeRoith
Derek
D
Cohen
Pinchas
P
D000230:Adenocarcinoma / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D013006:Growth Hormone / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D044967:Serum / Q000737:chemistry; D015398:Signal Transduction / Q000235:genetics; D047368:Tumor Burden
D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone