Hydrodynamic Shear Rate Regulates Melanoma-Leukocyte Aggregation, Melanoma Adhesion to the Endothelium, and Subsequent Extravasation

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Abstract
Adhesion to and subsequent extravasation through the endothelial lining of blood vessels is critical for tumor cells to establish metastases. Recent studies have indicated that polymorphonuclear neutrophils (PMNs) may enhance melanoma adhesion to the endothelium (EC) and subsequent extravasation under dynamic flow conditions. However, little is known about hydrodynamics involved in the tumor microenvironment within the microcirculation. In this study, effects of hydrodynamic flow on regulating melanoma cell adhesion to the EC have been investigated. Results indicate that under flow conditions, interactions between melanoma cells and the EC are distinctly different from PMN–EC interactions. Without expressions of surface integrins or sialylated molecules, most melanoma cells that express a high-level of intercellular adhesion molecule (ICAM-1) are not able to effectively adhere to the inflamed EC by themselves. Binding of melanoma cells and PMNs through ICAM-1 on melanoma cells and β2 integrins on PMNs has been shown to enhance melanoma cell arrest on the EC. Although PMN tethering on the EC is regulated by both the shear rate and shear stress, melanoma cell adhesion to the EC and subsequent extravasation via tethering PMN on the EC is predominantly regulated by shear rate, which partly is due to the shear-rate-dependent PMN-melanoma aggregation in shear flow. These findings provide a rationale and mechanistic basis for understanding of leukocyte–tumor cell interactions under flow conditions during tumor cell extravasation and metastasis.