Abstract
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.
Highlights
The formation of metastasis requires the successful completion of several sequential interrelated steps by the cancer cells [1]
The central objective of our investigation was to uncover the mechanisms by which E-selectin regulates the diapedesis of colon cancer cells under dynamic conditions that mimic the in vivo situation
Considering that the adhesion of cancer cells to the endothelium is a prerequisite to diapedesis, we first ascertained the role of E-selectin in mediating www.aacrjournals.org
Summary
The formation of metastasis requires the successful completion of several sequential interrelated steps by the cancer cells [1]. We have used a laminar flow chamber and a tissue-engineered human blood vessel to investigate the mechanism by which E-selectin regulates the diapedesis of HT-29 cells in dynamic and shear stress conditions that mimic the in vivo situation. E-selectin mediates the adhesion of colon cancer cells to endothelial cells under flow conditions.
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