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

Academic Article

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.
  • Published In

  • Oncotarget  Journal
  • Keywords

  • Antigens, Tumor-Associated, Carbohydrate, Cell Adhesion, Cell Line, Tumor, Cell Membrane, Endothelial Cells, Galectin 3, Humans, Integrin alpha3beta1, MAP Kinase Signaling System, Macromolecular Substances, Male, Neoplasm Metastasis, Prostatic Neoplasms, src-Family Kinases
  • Digital Object Identifier (doi)

    Author List

  • Glinskii OV; Li F; Wilson LS; Barnes S; Rittenhouse-Olson K; Barchi JJ; Pienta KJ; Glinsky VV
  • Start Page

  • 1382
  • End Page

  • 1389
  • Volume

  • 5
  • Issue

  • 5