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

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 β 2 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 shearrate-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.

Determining β2-Integrin and Intercellular Adhesion Molecule 1 Binding Kinetics in Tumor Cell Adhesion to Leukocytes and Endothelial Cells by a Gas-driven Micropipette Assay

“…␤ 2 -Integrin and ICAM-1 interaction facilitated tumor cell adhesion, and extravasation is a common mechanism for tumor cells. This paradigm has been found in melanoma (9,10,17,37,38), breast cancer (35,41,42), and colon adenocarcinoma (1,16). Thus, we also conducted a kinetics study between breast cancer cells MDA-MB-231 and PMNs.…”

“…Tethering and rolling of leukocytes on the endothelium are initiated by selectins and stabilized by ␤ 2 -integrins, which is followed by PECAM-1-induced transmigration through the extracellular matrix (13,14). Tumor cells are found to interact with PMNs under shear flow in a cone-plate viscometer (12,(15)(16)(17). Evidently, the interactions between ␤ 2 -integrin (LFA-1 or Mac-1) expressed on PMNs and intercellular adhesion molecule 1 (ICAM-1) expressed on TCs or ECs dominate both PMN-EC and PMN-TC adhesions (9,10,12).…”

“…The TC fraction in PMN-TC heterotypic aggregates measured was used to estimate the kinetic rates and binding affinities of ␤ 2 -integrin-ICAM-1 interactions (12). It was also found that PMNs tethering on ECs was regulated by both shear rate and shear stress (10,19), whereas TCs adhesion to PMNs was predominantly regulated by shear rate (9,10,17). Thus, it is critical from the viewpoint of two-dimensional kinetics of ␤ 2 -integrin-ICAM-1 interactions to compare the adhesions between PMN-EC and PMN-TC pairs and to further the understanding of leukocyte-facilitated tumor cell adhesion.…”

Circulating Melanoma Cells

“…Passive cell intravasation, where cells are simply dislodged from the primary tumour, occurs as a result of increased hemodynamic flow 22,31,32 . By contrast, active migration occurs in cells which have separated from their neighbours and actively migrate.…”

Microfluidic cytometers with integrated on-chip optical systems for red blood cell and platelet counting

“…1 Small-angle forward scatter (FSC) provides size information, whereas large-angle side scatter (SSC) offers information on internal properties (granularity and viability). Flow cytometry has been widely used for various applications such as clinical hematology diagnosis, 2,3 immunology, 4 and cancer biology. 5 However, the high cost, large size, mechanical complexity, large consumption of expensive agents, and requirements for professional operation of flow cytometry have limited its application.…”