Work

Endothelial integrin α3β1 stabilizes carbohydrate-mediated tumor/endothelial cell adhesion and induces macromolecular signaling complex formation at the endothelial cell membrane

Year: 2014

Type: article

Abstract: // Olga V. Glinskii 1,2 , Feng Li 1,2 , Landon S. Wilson 3 , Stephen Barnes 3 , Kate Rittenhouse-Olson 4 , Joseph J. Barchi Jr 5 , Kenneth J. Pienta 6 , Vladislav V. Glinsky 1,2 1 Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO 2 Department of Pathology and Anatomical Sciences and the Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 3 Department of Pharmacology and Toxicology and Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 4 Department of Biotechnical and Clinical Laboratory Sciences and the Department of Microbiology, University of Buffalo, Buffalo, NY 5 Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD 6 Department of Urology, The James Buchanan Brady Urological Institute, Departments of Oncology and Pharmacology and Molecular Sciences, The Johns Hopkins School of Medicine, Baltimore, MD Correspondence: Vladislav V. Glinsky, email: // Keywords : tumor metastasis, adhesion, Thomsen-Friedenreich antigen, galectin, integrin Received : February 10, 2014 Accepted : March 19, 2014 Published : March 20, 2014 Abstract Blood borne metastatic tumor cell adhesion to endothelial cells constitutes a critical rate-limiting step in hematogenous cancer metastasis. Interactions between cancer associated carbohydrate Thomsen-Friedenreich antigen (TF-Ag) and endothelium-expressed galectin-3 (Gal-3) have been identified as the leading molecular mechanism initiating tumor/endothelial cell adhesion in several types of cancer. However, it is unknown how these rather weak and transient carbohydrate/lectin mediated interactions are stabilized. Here, using Western blot and LC tandem mass spectrometry analyses of pull-downs utilizing TF-Ag loaded gold nanoparticles, we identified Gal-3, endothelial integrin α3β1, Src kinase, as well as 5 additional molecules mapping onto focal adhesion pathway as parts of the macromolecular complexes formed at the endothelial cell membranes downstream of TF-Ag/Gal-3 interactions. In a modified parallel flow chamber assay, inhibiting α3β1 integrin greatly reduced the strength of tumor/endothelial cell interactions without affecting the initial cancer cell adhesion. Further, the macromolecular complex induced by TF-Ag/Gal-3/α3β1 interactions activates Src kinase, p38, and ERK1/2, pathways in endothelial cells in a time- and α3β1-dependent manner. We conclude that, following the initial metastatic cell attachment to endothelial cells mediated by TF-Ag/Gal-3 interactions, endothelial integrin α3β1 stabilizes tumor/endothelial cell adhesion and induces the formation of macromolecular signaling complex activating several major signaling pathways in endothelial cells.

Source: Oncotarget

DOI: 10.18632/oncotarget.1837