IGFBP-3 is a metastasis suppression gene in prostate cancer

Cancer Res. 2011 Aug 1;71(15):5154-63. doi: 10.1158/0008-5472.CAN-10-4513. Epub 2011 Jun 22.


The insulin-like growth factor binding protein IGFBP-3 is a proapoptotic and antiangiogenic protein in prostate cancer (CaP). Epidemiologic studies suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers, but in vivo functional data are lacking. Here we show that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors but higher incidence of metastatic disease. Prostates in IGFBP-3 knockout mice (IGFBP-3KO mice) failed to undergo apoptosis after castration. Spontaneous prostate tumors did not develop in IGFBP-3KO mice, but splenic lymphomas occurred in 23% of female IGFBP-3KO mice by 80 weeks of age. To assess the effects of IGFBP-3 deficiency on prostate cancer development, we crossed IGFBP-3KO mice with a c-Myc-driven model of CaP that develops slow-growing, nonmetastatic tumors. By 24 weeks of age, well-differentiated prostate cancers were observed in all mice regardless of IGFBP-3 status. However, by 80 weeks of age IGFBP-3KO mice tended to exhibit larger prostate tumors than control mice. More strikingly, lung metastases were observed at this time in 55% of the IGFBP-3KO mice but none in the control animals. Cell lines established from IGFBP-3KO:Myc tumors displayed more aggressive phenotypes in proliferation, invasion, and colony formation assays, relative to control Myc tumor cell lines. In addition, Myc:IGFBP-3KO cells exhibited evidence of epithelial-mesenchymal transition. Our findings established a function for IGFBP-3 in suppressing metastasis in prostate cancer, and they also offered the first reported transgenic model of spontaneous metastatic prostate cancer for studies of this advanced stage of disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / secondary*
  • Androgens*
  • Animals
  • Apoptosis
  • Cell Line, Tumor / cytology
  • Crosses, Genetic
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Profiling
  • Genes, myc
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / deficiency
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / physiology*
  • Lung Neoplasms / secondary
  • Lymphoma, Non-Hodgkin / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Proteins / physiology*
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / secondary*
  • Orchiectomy
  • Phenotype
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Splenic Neoplasms / genetics
  • Tumor Burden
  • Tumor Stem Cell Assay


  • Androgens
  • Insulin-Like Growth Factor Binding Protein 3
  • Neoplasm Proteins