Collective migration of cancer-associated fibroblasts is enhanced by overexpression of tight junction-associated proteins claudin-11 and occludin.

Abstract

It has been suggested that cancer-associated fibroblasts (CAFs) positioned at the desmoplastic areas of various types of cancer are capable of executing a migratory program, characterized by accelerated motility and collective configuration. Since CAFs are reprogrammed derivatives of normal progenitors, including quiescent fibroblasts, we hypothesized that such migratory program could be context-dependent, thus being regulated by specific paracrine signals from the adjacent cancer population. Using the traditional scratch assay setup, we showed that only specific colon cancer cell lines (i.e. HT29) were able to induce collective CAF migration. By performing quantitative proteomics (SILAC), we identified a 2.7-fold increase of claudin-11, a member of the tight junction apparatus, in CAFs that exerted such collectivity in their migratory pattern. Further proteomic investigations of cancer cell line secretomes revealed a specific signature, involving TGF-β, as potential mediator of this effect. Normal colonic fibroblasts stimulated with TGF-β exerted myofibroblastic differentiation, occludin (OCLN) and claudin-11 (CLDN11) overexpression and cohort formation. Subsequently, inhibition of TGF-β attenuated all the previous effects. Immunohistochemistry of the universal tight junction marker occludin in a cohort of 30 colorectal adenocarcinoma patients defined a CAF subpopulation expressing tight junctions. Overall, these data suggest that cancer cells may induce CLDN11 overexpression and subsequent collective migration of peritumoral CAFs via TGF-β secretion.

• Authors: George S Karagiannis, David F Schaeffer, Chan-Kyung J Cho, Natasha Musrap, Punit Saraon, Ihor Batruch, Andrea Grin, Bojana Mitrovic, Richard Kirsch, Robert H Riddell, Eleftherios P Diamandis
• Journal: Molecular oncology (Mol Oncol) Vol. 8 Issue 2 Pg. 178-95 (Mar 2014) ISSN: 1878-0261 [Electronic] United States
• PMID: 24268521 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• CLDN11 protein, human
• Claudins
• Neoplasm Proteins
• Transforming Growth Factor beta

Topics

• Cell Line, Tumor
• Cell Movement
• Claudins (biosynthesis, genetics)
• Colonic Neoplasms (genetics, metabolism, mortality)
• Fibroblasts (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Proteins (biosynthesis, genetics)
• Tight Junctions (genetics, metabolism, pathology)
• Transforming Growth Factor beta (genetics, metabolism)