title: Angiotensin II type 1A receptor signaling facilitates tumor metastasis formation through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells.
abstract: Angiotensin II is involved in tumor growth; however, the precise mechanism is not known. Platelets also contribute to tumor growth, and angiotensin II type 1 receptor (AT1) is expressed on the platelet surface. We hypothesized that interaction of platelets with tumor cells through AT1 receptor signaling promotes tumor metastasis. B16F1 melanoma cells were intravenously injected into Agtr1a knockout mice (AT1a(-/-)) and wild-type littermates (WT); the AT1a(-/-) mice exhibited a reduction in lung colonies. Angiotensin II induced expression of P-selectin on platelets in WT but not in AT1a(-/-) mice. A selective P-selectin neutralizing antibody decreased lung colony numbers in WT but not in AT1a(-/-) mice. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) receptor in platelets at metastatic locus were lower in AT1a(-/-) mice. Treatment of neutralizing antibodies against VEGF and CXCR4 decreased lung colony numbers in WT but not in AT1a(-/-) mice. In AT1a(-/-) mice, and both mobilization of progenitor cells expressing CXCR4(+)VEGFR1(+) cells from bone marrow and their recruitment to lung tissues were suppressed. These results suggest that AT1A signaling plays a critical role in tumor metastasis through P-selectin-mediated interactions of platelets with tumor and endothelial cells and through the AT1A signaling-dependent production of VEGF and SDF-1, which may be involved in mobilization of CXCR4(+)VEGFR1(+) cells.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Amano
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Ogawa
authors.forename: Koji
authors.initials: K
authors.lastname: Eshima
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Oba
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Matsui
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kato
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fukui
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hidero
authors.initials: H
authors.lastname: Kitasato
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002450:Cell Communication / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000097:blood; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000097:blood / Q000473:pathology / Q000556:secondary*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019007:P-Selectin / Q000378:metabolism*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010976:Platelet Count; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D044140:Receptor, Angiotensin, Type 1; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D040281:Vascular Endothelial Growth Factor Receptor-1