Matrix-bound PAI-1 supports cell blebbing via RhoA/ROCK1 signaling

• Published in: PloS one Vol. 7; no. 2; p. e32204
• Main Authors: Cartier-Michaud, Amandine, Malo, Michel, Charrière-Bertrand, Cécile, Gadea, Gilles, Anguille, Christelle, Supiramaniam, Ajitha, Lesne, Annick, Delaplace, Franck, Hutzler, Guillaume, Roux, Pierre, Lawrence, Daniel A, Barlovatz-Meimon, Georgia
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.02.2012; Public Library of Science (PLoS)
• Subjects: Biology; Cancer; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Surface Extensions - drug effects; Cell Surface Extensions - metabolism; Collagen; Colorectal cancer; Colorectal carcinoma; Computer Science; Computer Simulation; Environmental changes; Enzyme Activation - drug effects; Enzymes; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Humans; Immobilized Proteins - pharmacology; Immunoblotting; Immunofluorescence; Kinases; Mesenchyme; Mesoderm - drug effects; Mesoderm - pathology; Metastases; Metastasis; Models, Biological; Morphology; Phosphorylation; Physiological aspects; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen Activator Inhibitor 1 - pharmacology; Plasminogen activator inhibitors; Protein Binding - drug effects; Proteins; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; RhoA protein; Signal Transduction - drug effects; Signaling; Stem cells; Tumors; Urokinase-Type Plasminogen Activator - pharmacology; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0032204

The microenvironment of a tumor can influence both the morphology and the behavior of cancer cells which, in turn, can rapidly adapt to environmental changes. Increasing evidence points to the involvement of amoeboid cell migration and thus of cell blebbing in the metastatic process; however, the cues that promote amoeboid cell behavior in physiological and pathological conditions have not yet been clearly identified. Plasminogen Activator Inhibitor type-1 (PAI-1) is found in high amount in the microenvironment of aggressive tumors and is considered as an independent marker of bad prognosis. Here we show by immunoblotting, activity assay and immunofluorescence that, in SW620 human colorectal cancer cells, matrix-associated PAI-1 plays a role in the cell behavior needed for amoeboid migration by maintaining cell blebbing, localizing PDK1 and ROCK1 at the cell membrane and maintaining the RhoA/ROCK1/MLC-P pathway activation. The results obtained by modeling PAI-1 deposition around tumors indicate that matrix-bound PAI-1 is heterogeneously distributed at the tumor periphery and that, at certain spots, the elevated concentrations of matrix-bound PAI-1 needed for cancer cells to undergo the mesenchymal-amoeboid transition can be observed. Matrix-bound PAI-1, as a matricellular protein, could thus represent one of the physiopathological requirements to support metastatic formation.