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METHODS IN CELL PHYSIOLOGY

Two-dimensional kinetics of β₂-integrin and ICAM-1 bindings between neutrophils and melanoma cells in a shear flow

¹Department of Bioengineering, The Pennsylvania State University, University Park, Pennsylvania; and ²National Microgravity Laboratory and Center for Biomechanics and Bioengineering, Institute of Mechanics, Chinese Academy of Sciences, Beijing, People's Republic of China

Submitted 12 June 2007 ; accepted in final form 13 January 2008

Cell adhesion, mediated by specific receptor-ligand interactions, plays an important role in biological processes such as tumor metastasis and inflammatory cascade. For example, interactions between β₂-integrin (lymphocyte function-associated antigen-1 and/or Mac-1) on polymorphonuclear neutrophils (PMNs) and ICAM-1 on melanoma cells initiate the bindings of melanoma cells to PMNs within the tumor microenvironment in blood flow, which in turn activate PMN-melanoma cell aggregation in a near-wall region of the vascular endothelium, therefore enhancing subsequent extravasation of melanoma cells in the microcirculations. Kinetics of integrin-ligand bindings in a shear flow is the determinant of such a process, which has not been well understood. In the present study, interactions of PMNs with WM9 melanoma cells were investigated to quantify the kinetics of β₂-integrin and ICAM-1 bindings using a cone-plate viscometer that generates a linear shear flow combined with a two-color flow cytometry technique. Aggregation fractions exhibited a transition phase where it first increased before 60 s and then decreased with shear durations. Melanoma-PMN aggregation was also found to be inversely correlated with the shear rate. A previously developed probabilistic model was modified to predict the time dependence of aggregation fractions at different shear rates and medium viscosities. Kinetic parameters of β₂-integrin and ICAM-1 bindings were obtained by individual or global fittings, which were comparable to respectively published values. These findings provide new quantitative understanding of the biophysical basis of leukocyte-tumor cell interactions mediated by specific receptor-ligand interactions under shear flow conditions.

heterotypic cell aggregation; adhesion molecule; leukocyte; tumor cell; reverse rate; binding affinity; probabilistic model; polymorphonuclear neutrophils; intercellular adhesion molecule-1

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