IGFBP-5 enhances epithelial cell adhesion and protects epithelial cells from TGFβ1-induced mesenchymal invasion

A Vijayan, D Guha, A Fasal, I Kaziri, C C Mooney, L Bennett, A Sureshbabu, E Tonner, J Beattie, J Edwards, D J Flint

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18 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)2774-2785
Number of pages12
JournalInternational Journal of Biochemistry and Cell Biology
Volume45
Issue number12
Early online date11 Oct 2013
DOIs
Publication statusPublished - 2013

Keywords

  • breast cancer
  • boundaries
  • IGFBP-5
  • TGF1
  • adhesion
  • migration

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