title: IGFBP-3 is a metastasis suppression gene in prostate cancer.
abstract: 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.
authors.affiliation: Mattel Children's Hospital, CA, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Mehta
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.forename: Colette
authors.initials: C
authors.lastname: Galet
authors.forename: Vladislava
authors.initials: V
authors.lastname: Paharkova
authors.forename: Junxiang
authors.initials: J
authors.lastname: Wan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Said
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Sohn
authors.forename: Gregory
authors.initials: G
authors.lastname: Lawson
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Cobb
authors.forename: Kuk-Wha
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary*; D000728:Androgens; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor / Q000166:cytology; D003433:Crosses, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000556:secondary; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009363:Neoplasm Proteins / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000556:secondary*; D009919:Orchiectomy; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013160:Splenic Neoplasms / Q000235:genetics; D047368:Tumor Burden; D014410:Tumor Stem Cell Assay
chemical_list: D000728:Androgens; D018972:Insulin-Like Growth Factor Binding Protein 3; D009363:Neoplasm Proteins