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Title: Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis

Author
item KAPLAN-LEFKO, P - BAYLOR COLLEGE MED
item SUTHERLAND, B - FRED HUTCHINSON CANCER CT
item EVAGELOU, A - BAYLOR COLLEGE MED
item HADSELL, D - BAYLOR COLLEGE MED
item BARRIOS, R - BAYLOR COLLEGE MED
item FOSTER, B - ROSWELL PARK CANCER INST
item DEMAYO, F - BAYLOR COLLEGE MED
item GREENBERG, N - BAYLOR COLLEGE MED

Submitted to: Oncogene
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/17/2007
Publication Date: 5/1/2008
Citation: Kaplan-Lefko, P.J., Sutherland, B.W., Evagelou, A.I., Hadsell, D.L., Barrios, R.J., Foster, B.A., Demayo, F., Greenberg, N.M. 2008. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene. 27(20):2868-2876.

Interpretive Summary: IGF-I is a growth factor that is known to be linked with increased risk for both breast and prostate cancer. In this study, transgenic mice were used to determine if overexpression of IGF-I in the prostate gland would cause prostate cancer. The results show that overexpression of IGF-I caused modest changes in the development of the prostate gland, but not prostate cancer. These studies will be useful for learning the mechanisms through which growth factors cause cancer in men and women.

Technical Abstract: The insulin-like growth factor-1 (IGF-1) signaling axis is important for cell growth, differentiation, and survival, and increased serum IGF is a risk factor for prostate and other cancers. To study IGF-1 action on the prostate, we created transgenic (PB-Des) mice that specifically express human IGF-1(des) in prostate epithelial cells. This encodes a mature isoform of IGF-1 with decreased affinity for IGF binding proteins (IGFBP) due to a 3-amino acid deletion in the N terminus. Expression of IGF-1(des) was sufficient to cause hyperplastic lesions in all mice; however, the well-differentiated lesions did not progress to adenocarcinoma within a year. Remarkably, crossing the PB-Des mice to an established model of prostate cancer delayed progression of organ-confined tumors and emergence of metastatic lesions in young mice. While dissemination of metastatic lesions was widespread in old bigenic mice we did not detect IGF-1(des) in poorly differentiated primary tumors or metastatic lesions. Expression of endogenous IGF-1 and levels of P-Akt and P-Erk were reduced independent of age. These data suggest that increased physiologic levels of IGF-1 facilitate the emergence of hyperplastic lesions while imposing a strong IGF-1-dependent differentiation block. Selection against IGF-1 action appears requisite for progression of localized disease and metastogenesis.