1. ¹Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
2. ²Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
3. ³Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
4. ⁴Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
5. ⁵Department of Pathology, Baylor College of Medicine, Houston, TX, USA
6. ⁶Pharmacology and Therapeutics Department, Roswell Park Cancer Institute, Buffalo, NY, USA
7. ⁷Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
8. ⁸Department of Pharmacology, University of Washington, Seattle, WA, USA

Correspondence: Dr NM Greenberg, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. E-mail: ngreenberg@fhcrc.org

⁹Current address: AMGEN, Thousand Oaks CA, 91320

¹⁰Current address: Biomedical Research Centre, UBC, Vancouver BC, Canada

¹¹Current address: University of Toronto, Toronto, Ontario, Canada

Received 3 December 2006; Revised 17 October 2007; Accepted 17 October 2007; Published online 19 November 2007.

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.