Mechanisms by which E-selectin regulates diapedesis of colon cancer cells under flow conditions.
Diapedesis, the passage of circulating tumor cells across the endothelium, is a critical determinant in most cases of metastasis. Using a laminar flow chamber and a tissue-engineered blood vessel, we found that E-selectin is required not only for the initial adhesion and rolling of circulating HT-29 colon cancer cells on the endothelium but also for their subsequent diapedesis. These processes require both the intracellular and extracellular domains of E-selectin. We also identified three distinct mechanisms by which circulating cancer cells interact with E-selectin to initiate their diapedesis: formation of a mosaic between cancer cells and endothelial cells, paracellular diapedesis at the junction of three endothelial cells, and transcellular diapedesis. We also obtained evidence indicating that E-selectin-dependent paracellular extravasation is independent of intercellular adhesion molecule and vascular cell adhesion molecule and that it requires the activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase downstream of E-selectin. This is supported by the observation that the adenoviral-mediated expression of the E-selectin mutant Y603F is associated with both an inhibition of ERK and paracellular extravasation. Our study is the first to clearly establish, under dynamic and shear stress conditions, how E-selectin regulates diapedesis of circulating cancer cells. These results provide new insights in understanding the metastatic process.
Tremblay
Pierre-Luc
PL
Laboratoire d'Organogenèse Expérimentale, Centre Hospitalier Affilié Universitaire de Québec, Canada.
Huot
Jacques
J
Auger
François A
FA
D001808:Blood Vessels / Q000502:physiology; D002448:Cell Adhesion; D018929:Cell Culture Techniques / Q000379:methods; D002465:Cell Movement; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology*; D019040:E-Selectin / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology; D004780:Environment, Controlled; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D023822:Tissue Engineering; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019040:E-Selectin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases