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Mechanisms by which E-Selectin Regulates Diapedesis of Colon Cancer Cells under Flow Conditions

¹ Laboratoire d'Organogenèse Expérimentale, Centre Hospitalier Affilié Universitaire de Québec; and ² Le Centre de Recherche en Cancérologie de l'Université Laval, Québec, Canada

Requests for reprints: François A. Auger, Department of Surgery, Université Laval/Laboratoire d'Organogenèse Expérimentale, Centre Hospitalier Affilié Universitaire de Québec, 1050 Chemin St-Foy, Québec, G1S 4L8, Canada. Phone: 418-682-7663; Fax: 418-682-8000; E-mail: Francois.Auger{at}chg.ulaval.ca.

Key Words: E-selectin • diapedesis • MAPK • colon cancer

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. [Cancer Res 2008;68(13):5167–76]