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1 Bioengineering, Pennsylvania State University, University Park, PA, USA
2 The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
3 Bioengineering, Pennsylvania State University, University Park, PA, USA; The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
* To whom correspondence should be addressed. E-mail: cxd23{at}psu.edu.
Previously, we found neutrophils (PMNs) increased melanoma cell extravasation under flow conditions (Intl J Cancer 106:713-722). In this study, we characterized the effect of hydrodynamic shear on PMN-facilitated melanoma extravasation using a novel flow-migration assay. The effect of shear stress and shear rate on PMN-facilitated melanoma extravasation was studied by increasing the medium viscosity with dextran to increase shear stress independently of shear rate. Under fixed shear rate conditions, melanoma cell extravasation did not change significantly. In contrast, the extravasation level increased at a fixed shear stress but with a decreasing shear rate. PMN-melanoma aggregation and adhesion to the endothelium via 
2-integrin/ICAM-1 interactions was also studied. LFA-1 (CD11a/CD18) influenced the capture phase of PMN binding to both melanoma cells and the endothelium, while Mac-1 (CD11b/CD18) affected prolonged PMN-melanoma aggregation. Blocking E-selectin or ICAM-1 on the endothelium or ICAM-1 on the melanoma surface reduced PMN-facilitated melanoma extravasation. We have found PMN-melanoma adhesion is correlated with the inverse of shear rate whereas the PMN-endothelial adhesion correlated with shear stress. Interleukin-8 (IL-8) also influenced PMN-melanoma cell adhesion. Functional blocking of the PMN IL-8 receptors, CXCR1 and CXCR2, decreased the level of Mac-1 up-regulation on PMNs while in contact with melanoma cells and reduced melanoma extravasation. We have found PMN-facilitated melanoma adhesion to be a complex multi-step process that is regulated by both microfluid-mechanics and biology.
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