title: IGFBP-5 enhances epithelial cell adhesion and protects epithelial cells from TGFβ1-induced mesenchymal invasion.
abstract: TGFβ1 is a major fibrotic factor and its actions involve induction of epithelial cell death, together with the stimulation and transdifferentiation of fibroblasts into collagen- and fibronectin-secreting myofibroblasts. These actions of TGFβ1 are also consistent with a pro-metastatic role, by aiding epithelial cell escape through mesenchymal tissues. Recently IGFBP-5 has been described as a pro-fibrotic (pro-metastatic?) agent and the aim of this study was to compare and contrast the actions of IGFBP-5 with TGFβ1. We used NMuMG cells and cloned stable epithelial and mesenchymal lines from the parent cells. TGFβ1 induced apoptosis and/or EMT in the epithelial cells, whereas it enhanced mesenchymal cell survival and migration. IGFBP-5, in contrast, enhanced both cell-cell and cell-ECM adhesion and also improved wound closure in epithelial cells whereas, in mesenchymal cells, IGFBP-5 decreased adhesion and migration. Furthermore, IGFBP-5 was able to antagonise the actions of TGFβ1. In a co-culture model simulating epithelial-mesenchymal boundaries, IGFBP-5 was able to antagonise the disruptive transgressions induced by TGFβ1. Overall, these findings suggest that IGFBP-5 is important in maintaining epithelial-mesenchymal boundaries and thus may limit metastasis and fibrosis by inducing an orderly repair mechanism, very distinct from the fibrotic disruption induced by TGFβ1. A role for IGFBP-5 in the inhibition of metastasis is supported by immunohistochemical studies of breast cancer microarrays, where we show that elevated IGFBP-5 expression is associated with increased disease-free survival.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Vijayan
authors.forename: D
authors.initials: D
authors.lastname: Guha
authors.forename: F
authors.initials: F
authors.lastname: Ameer
authors.forename: I
authors.initials: I
authors.lastname: Kaziri
authors.forename: C C
authors.initials: CC
authors.lastname: Mooney
authors.forename: L
authors.initials: L
authors.lastname: Bennett
authors.forename: A
authors.initials: A
authors.lastname: Sureshbabu
authors.forename: E
authors.initials: E
authors.lastname: Tonner
authors.forename: J
authors.initials: J
authors.lastname: Beattie
authors.forename: G J
authors.initials: GJ
authors.lastname: Allan
authors.forename: J
authors.initials: J
authors.lastname: Edwards
authors.forename: D J
authors.initials: DJ
authors.lastname: Flint
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018975:Insulin-Like Growth Factor Binding Protein 5; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1
keywords: Adhesion; Cancer; IGFBP-5; Migration; TGFβ1