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

P. J. Kaplan-Lefko, B. W. Sutherland, A. I. Evangelou, D. L. Hadsell, Roberto Barrios, B. A. Foster, F. DeMayo, N. M. Greenberg

Research output: Contribution to journalArticle

23 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)2868-2876
Number of pages9
JournalOncogene
Volume27
Issue number20
DOIs
StatePublished - May 1 2008

Keywords

  • Akt
  • IGF-1
  • Prostate
  • TRAMP
  • Transgenic

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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