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-1des 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-1des 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-1des 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.
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Acknowledgements
We would like to thank Tsuey-Ming Chen for help with immunoblotting, Diane Gentry and Caroline Castile for animal care and histology support and Jeffrey M Rosen and Stephen Plymate for their many helpful insights and constructive commentaries. This work was supported by grants from the National Cancer Institute CA82807 and CA84296 (to NMG), CA74589 (to PJK-L), and The Prostate Cancer Foundation (to PJK-L and NMG).
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Kaplan-Lefko, P., Sutherland, B., Evangelou, A. et al. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene 27, 2868–2876 (2008). https://doi.org/10.1038/sj.onc.1210943
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DOI: https://doi.org/10.1038/sj.onc.1210943
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