TY - JOUR
T1 - Collective migration of cancer-associated fibroblasts is enhanced by overexpression of tight junction-associated proteins claudin-11 and occludin
AU - Karagiannis, George S.
AU - Schaeffer, David F.
AU - Cho, Chan Kyung J.
AU - Musrap, Natasha
AU - Saraon, Punit
AU - Batruch, Ihor
AU - Grin, Andrea
AU - Mitrovic, Bojana
AU - Kirsch, Richard
AU - Riddell, Robert H.
AU - Diamandis, Eleftherios P.
N1 - Funding Information:
George S. Karagiannis is supported by University Health Network and Mount Sinai Hospital , Toronto, ON, Canada. The authors kindly thank Chris Smith for technical assistance in mass spectrometry, Antoninus Soosaipillai for technical and laboratory assistance, and Maria Pavlou, Shalini Makawita, Yiannis Prassas and Uros Kuzmanov for helpful suggestions.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - Cancer-associated fibroblasts
KW - Claudin-11
KW - Colorectal cancer
KW - Migration
KW - SILAC
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U2 - 10.1016/j.molonc.2013.10.008
DO - 10.1016/j.molonc.2013.10.008
M3 - Article
C2 - 24268521
AN - SCOPUS:84894348540
SN - 1574-7891
VL - 8
SP - 178
EP - 195
JO - Molecular Oncology
JF - Molecular Oncology
IS - 2
ER -
