Role of Eicosanoids in Tumor Cell-Platelet-Endothelial Cell Interactions

Abstract

Metastases represent perhaps the single most important hindrance to improved cancer patient survival. The formation of metastases is the culmination of a complex series of tumor cell-host interactions called the metastatic cascade (Figure 1; 1,2). During tumor progression, tumor cells become separated from the primary tumor mass and invade into the surrounding tissue. Occasionally, tumor cells will invade blood vessels or lymphatics (intravasation) and are readily disseminated throughout the host. A relatively small percentage of the circulating tumor cells will arrest at the vessel wall and invade into the surrounding tissue (extravasation) to establish a secondary tumor site (3–5). The interaction of the circulating tumor cells with host immune cells may result in destruction of the tumor cells, whereas interaction with host platelets and/or blood coagulation components may enhance the metastatic process. Evidence for the involvement of platelets in metastasis has been demonstrated by several investigators (for review see 6,7). Enhancement of tumor cell arrest and adhesion to the vessel wall by platelets has been postulated as the mechanism for this phenomenon, but its exact nature is undetermined. Because of the potent effects of arachidonic acid metabolites (i.e., prostacyclin and thromboxane A₂) on platelet function, we have hypothesized that tumor cells shift the balance between these metabolites in favor of platelet aggregation (8). We have previously proposed the use of modifiers of arachidonic acid metabolism as antimetastatic agents, although the efficacy of antimetastatic therapy with these modifiers has been inconsistent. Prostacyclin (PGI₂) has been recently shown to reduce the incidence of pulmonary.