title: VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice.
abstract: Pulmonary metastasis is a frequent cause of poor outcome in cancer patients. The formation of pulmonary metastasis is greatly facilitated by recruitment of myeloid cells, which are crucial for tumor cell survival and extravasation. During inflammation, homing of myeloid cells is mediated by endothelial activation, raising the question of a potential role for endothelial activation in myeloid cell recruitment during pulmonary metastasis. Here, we show that metastatic tumor cell attachment causes the induction of the endothelial activation markers vascular cell adhesion molecule-1 (VCAM-1) and vascular adhesion protein-1 (VAP-1). Induction of VCAM-1 is dependent on tumor cell-clot formation, decreasing upon induction of tissue factor pathway inhibitor or treatment with hirudin. Furthermore, inhibition of endothelial activation with a VCAM-1 blocking antibody or a VAP-1 small molecule inhibitor leads to reduced myeloid cell recruitment and diminished tumor cell survival and metastasis without affecting tumor cell adhesion. Simultaneous inhibition of VCAM-1 and VAP-1 does not result in further reduction in myeloid cell recruitment and tumor cell survival, suggesting that both act through closely related mechanisms. These results establish VCAM-1 and VAP-1 as mediators of myeloid cell recruitment in metastasis and identify VAP-1 as a potential target for therapeutic intervention to combat early metastasis.
authors: Department of Oncology, Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors: Špela
authors: Š
authors: Ferjančič
authors: Ana M
authors: AM
authors: Gil-Bernabé
authors: Sally A
authors: SA
authors: Hill
authors: Philip D
authors: PD
authors: Allen
authors: Peter
authors: P
authors: Richardson
authors: Tim
authors: T
authors: Sparey
authors: Edward
authors: E
authors: Savory
authors: Jane
authors: J
authors: McGuffog
authors: Ruth J
authors: RJ
authors: Muschel
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000276:immunology*; D000818:Animals; D001777:Blood Coagulation; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008175:Lung Neoplasms / Q000097:blood / Q000276:immunology / Q000473:pathology* / Q000556:secondary*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*
chemical_list: D015815:Cell Adhesion Molecules; D019010:Vascular Cell Adhesion Molecule-1; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse