Thromboxane A 2 receptor signaling facilitates tumor colonization through P ‐selectin‐mediated interaction of tumor cells with platelets and endothelial cells

Thromboxane A 2 ( TXA 2 ) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product, prostaglandin H (2), as the substrate. TXA 2 was shown to enhance tumor metastasis, but the underlying mechanism remains unclear. B 16 F 1 melanoma cells were intravenously injected into TXA 2 receptor ( TP ) knockout mice ( TP −/− ) and wild‐type littermates ( WT ). TP −/− showed a reduction in B 16 F 1 lung colonization and mortality rate, which were associated with a decreased number of platelets. Platelet activation as assessed by P ‐selectin expression was suppressed in TP −/− . A selective P ‐selectin neutralizing antibody decreased the lung colonization in WT mice, but not in TP −/− . The expression of P ‐selectin glycoprotein ligand‐1 in B 16 F 1 and HUVEC were enhanced by treatment with U 46619, a thromboxane analog. The plasma levels of vascular endothelial growth factor ( VEGF ) and stromal‐derived factor ( SDF )‐1 were lower in TP −/− . In TP −/− , the mobilization of progenitor cells expressing CXCR 4 + VEGFR 1 + from bone marrow and the recruitment of those cells to lung tissues were suppressed. These results suggest that TP signaling plays a critical role in tumor colonization through P‐selectin‐mediated interactions between platelets‐tumor cells and tumor cells‐endothelial cells through the TP signaling‐dependent production of VEGF and SDF ‐1, which might be involved in the mobilization of VEGFR 1 + CXCR 4 + cells. Blockade of TP signaling might be useful in the treatment of tumor metastasis. ( Cancer Sci 2012; 103: 700–707)