title: Thromboxane A₂ receptor signaling facilitates tumor colonization through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells.
abstract: 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. B16F1 melanoma cells were intravenously injected into TXA(2) receptor (TP) knockout mice (TP(-/-) ) and wild-type littermates (WT). TP(-/-) showed a reduction in B16F1 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 B16F1 and HUVEC were enhanced by treatment with U46619, 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 CXCR4(+) VEGFR1(+) 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 VEGFR1(+) CXCR4(+) cells. Blockade of TP signaling might be useful in the treatment of tumor metastasis.
authors.affiliation: Department of Thoracic Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Matsui
authors.forename: Hideki
authors.initials: H
authors.lastname: Amano
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Koji
authors.initials: K
authors.lastname: Eshima
authors.forename: Tastunori
authors.initials: T
authors.lastname: Suzuki
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Ogawa
authors.forename: Akira
authors.initials: A
authors.lastname: Iyoda
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Satoh
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kato
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hidero
authors.initials: H
authors.lastname: Kitasato
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D018827:Carcinoma, Lewis Lung / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D008546:Melanoma, Experimental / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D019007:P-Selectin / Q000378:metabolism*; D015539:Platelet Activation; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D044244:Receptors, Thromboxane A2, Prostaglandin H2