Effects of the Tumor-Leukocyte Microenvironment on Melanoma–Neutrophil Adhesion to the Endothelium in a Shear Flow

Abstract

The primary cause of cancer mortality is not attributed to primary tumor formation, but rather to the growth of metastases at distant organ sites. Tumor cell adhesion to blood vessel endothelium (EC) and subsequent transendothelial migration within the circulation are critical components of the metastasis cascade. Previous studies have shown polymorphonuclear neutrophils (PMNs) may facilitate melanoma cell adhesion to the EC and subsequent extravasation under flow conditions. The melanoma cell-PMN interactions are found to be mediated by the binding between intercellular adhesion molecule-1 (ICAM-1) on melanoma cells and β(2) integrin on PMNs and by endogenously secreted interleukin 8 (IL-8) within the tumor-leukocyte microenvironment. In this study, the effects of fluid convection on the IL-8-mediated activation of PMNs and the binding kinetics between PMNs and melanoma cells were investigated. Results indicate that the shear rate dependence of PMN-melanoma cell adhesion and melanoma cell extravasation is due, at least partly, to the convection of tumor-secreted proinflammatory cytokine IL-8.