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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008-07, Vol.68 (13), p.5167-5176
• Main Authors: TREMBLAY, Pierre-Luc, HUOT, Jacques, AUGER, Francois A
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Blood Vessels - physiology; Cell Adhesion; Cell Culture Techniques - methods; Cell Movement; Cells, Cultured; Colonic Neoplasms - pathology; E-Selectin - genetics; E-Selectin - physiology; Endothelial Cells - physiology; Environment, Controlled; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; HT29 Cells; Humans; Medical sciences; Neoplastic Cells, Circulating - pathology; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tissue Engineering; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-1229

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.