? The events that mediate the initial steps in melanoma extravasation, adhesion of melanoma cancer cells to the endothelium within the dynamic circulation, are not well defined. Studies from our group, as well as others, have suggested that melanoma cell lines inefficiently bind endothelial cells underflow conditions and may require assistance for adhesion. We propose that neutrophils (PMNs), through direct cell-cell interaetions and the elaboration of soluble factors, directly participate in this process by inducing tumor cell expression of chemokines and cellular adhesion molecules. These tumor-derived factors contribute to a microenvironment that enhances the ability of melanoma cells to adhere to endothelium within the circulation. Preliminary data are presented that support this model including results that show PMNs aggregate with melanoma cells, PMNs stimulate IL-8 production in melanoma cell lines and, most importantly, PMNs facilitate melanoma cell adhesion to endothelial molecules under flow conditions and subsequent extravasation.
We aim to extend these studies by (1) developing an experimental system that will permit in vitro investigations of melanoma cell adhesion to endothelium and subsequent transmigration, especially in the presence of PMNs under flow conditions; (2) determining what cytokines and chemokines are produced by melanoma cells following PMN induction and their role in mediating tumor cell adhesion and migration; and (3) characterizing the signal transduction cascades and transcriptional activators in melanoma cells induced by PMNs that facilitate melanoma adhesion and migration under flow conditions. We wilI also examine the effect of endothelial activation on regulating melanoma cell adhesion and migration, especially under the influence of PMNs. Therefore, these studies will provide a better understanding of the potential accessory role of PMNs in melanoma cell binding and insight into general mechanisms of tumor cell adhesion under dynamic flow conditions that mimic a blood capillary. Furthermore, since adhesion is a critical step in tumor metastasis these studies may identify novel therapeutic targets against invasive melanomas. ? ?
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