Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10914740 | Molecular Oncology | 2014 | 18 Pages |
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.
Keywords
ICCMWLCALDMEHPOCLNIGPECMTGF-βPLAUCAFlamb1mono-(2-ethylhexyl) phthalateImmunocytochemistryIHCImmunohistochemistrystable isotope labeling with amino acids in cell culturetransforming growth factor-betaEMTconditioned mediaColorectal cancerSILACOccludinurokinase-type plasminogen activatorCancer-associated fibroblastscancer-associated fibroblastExtracellular matrixMigrationCaldesmonClaudin-11epithelial-to-mesenchymal transition
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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,