Inhibition of cytokine-induced microvascular arrest of tumor cells by recombinant endostatin prevents experimental hepatic melanoma metastasis.
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.
Mendoza
Lorea
L
Dominion-Pharmakine Ltd., Bizkaia Technology Park, Bizkaia, Spain.
Valcárcel
María
M
Carrascal
Teresa
T
Egilegor
Eider
E
Salado
Clarisa
C
Sim
B Kim Lee
BK
Vidal-Vanaclocha
Fernando
F
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
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1