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: A Vijayan, D Guha, F Ameer, I Kaziri, C C Mooney, L Bennett, A Sureshbabu, E Tonner, J Beattie, G J Allan, J Edwards, D J Flint
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 45 Issue 12 Pg. 2774-85 (Dec 2013) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 24120850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Insulin-Like Growth Factor Binding Protein 5
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Breast Neoplasms (pathology)
• Cell Adhesion (physiology)
• Cells, Cultured
• Disease-Free Survival
• Epithelial Cells (cytology, drug effects, metabolism, pathology)
• Epithelial-Mesenchymal Transition (drug effects, physiology)
• Female
• Humans
• Insulin-Like Growth Factor Binding Protein 5 (genetics, metabolism, pharmacology)
• Mice
• NIH 3T3 Cells
• Transforming Growth Factor beta1 (genetics, metabolism, pharmacology)