Crossing the endothelium: E-selectin regulates tumor cell migration under flow conditions

Abstract

Diapedesis is a vital part of tumor metastasis, whereby tumor cells attach to and cross the endothelium to enter the circulation. Specific adhesion molecules, expressed by both the tumor and endothelial cells, mediate this process. This review summarizes recent findings regarding the mechanisms by which colon cancer cells migrate through the endothelium under flow conditions mediated by E-selectin. Using a laminar flow chamber and a tissue engineered human blood vessel, E-selectin was found to regulate initial attachment and rolling of colon cancer cells and also the subsequent diapedesis through the endothelium. Three different mechanisms of diapedesis were reported to be regulated by E-selectin; the formation of a mosaic chimeric layer of tissue, paracellular diapedesis between endothelial cells and transcellular diapedesis, in which tumor cells were transported via large vacuoles within the endothelial cells. Moreover activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase by E-selectin was further required for paracellular diapedesis. This study is the first to report these observations under dynamic and shear stress conditions.

Figure 1

Schematic representation of the three mechanisms that colon cancer cells use during diapedesis of the endothelium. Under flow conditions, tumor cells initially form loose attachments with the endothelium, prior to rolling and forming firm attachments, mediated by specific adhesion molecules such as E-selectin. Following firm adhesion, tumor cells initiate diapedesis by (1) migrating between the junctions of endothelial cells (paracellular diapedesis), (2) forming a mosaic chimeric layer of both cell types (although this may not lead to complete diapedesis) and (3) passaging through the endothelial cells in large vacuoles (transcellular diapedesis).