title: Inhibition of cytokine-induced microvascular arrest of tumor cells by recombinant endostatin prevents experimental hepatic melanoma metastasis.
abstract: We investigated effects of endostatin (ES) in the prometastatic microenvironment of inflammation occurring during the microvascular phase of cancer cell infiltration in the liver. We used a model of intrasplenic injection of B16 melanoma (B16M) cells leading to hepatic metastasis through vascular cell adhesion molecule-(VCAM-1)-mediated capillary arrest of cancer cells via interleukin-18 (IL-18)-dependent mechanism. We show that administration of 50 mg/kg recombinant human (rh) ES 30 min before B16M, plus repetition of same dose for 3 additional days decreased metastasis number by 60%. A single dose of rhES before B16M injection reduced hepatic microvascular retention of luciferase-transfected B16M by 40% and inhibited hepatic production of tumor necrosis factor alpha (TNF-alpha) and IL-18 and VCAM-1 expression by hepatic sinusoidal endothelia (HSE). Consistent with these data, rhES inhibited VCAM-1-dependent B16M cell adhesion to primary cultured HSE receiving B16M conditioned medium, and it abolished the HSE cell production of TNF-alpha and IL-18 induced by tumor-derived vascular endothelial cell growth factor (VEGF). rhES abrogated recombinant murine VEGF-induced tyrosine phosphorylation of KDR/flk-1 receptor in HSE cells, preventing the proinflammatory action of tumor-derived VEGF on HSE. rhES also abolished hepatic production of TNF-alpha, microvascular retention of luciferase-transfected B16M, and adhesion of B16M cells to isolated HSE cells, all of them induced in mice given 5 micro g/kg recombinant murine VEGF for 18 h. This capillary inflammation-deactivating capability constitutes a nonantiangiogenic antitumoral action of endostatin that decreases cancer cell arrest within liver microvasculature and prevents metastases promoted by proinflammatory cytokines induced by VEGF.
authors.affiliation: Dominion-Pharmakine Ltd., Bizkaia Technology Park, Bizkaia, Spain.
authors.forename: Lorea
authors.initials: L
authors.lastname: Mendoza
authors.forename: María
authors.initials: M
authors.lastname: Valcárcel
authors.forename: Teresa
authors.initials: T
authors.lastname: Carrascal
authors.forename: Eider
authors.initials: E
authors.lastname: Egilegor
authors.forename: Clarisa
authors.initials: C
authors.lastname: Salado
authors.forename: B Kim Lee
authors.initials: BK
authors.lastname: Sim
authors.forename: Fernando
authors.initials: F
authors.lastname: Vidal-Vanaclocha
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D043169:Endostatins / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1