INTRAVITAL VIDEOMICROSCOPIC EVIDENCE FOR REGULATION OF METASTASIS BY THE HEPATIC MICROVASCULATURE - EFFECTS OF INTERLEUKIN-1-ALPHA ON METASTASIS AND THE LOCATION OF B16F1 MELANOMA CELL ARREST

There have been few reported visual observations of metastatic cancer cell arrest in vivo. To seek evidence that inducible vascular adhesive properties can regulate hepatic metastasis, groups of 9-14 c57b1/6 mi ce were given 1.5 mu g of interleukin-1 alpha (IL-1 alpha) 4 h before the injection of 3 X 10(5) B16F1 melanoma cells into a mesenteric vein . After 7 days, these mice had an 11-22-fold greater hepatic tumor bur den than controls given i.p. saline. In both groups, small metastases were seen in the portal tract region. Twice as many I-125-labeled UdR- labeled B16F1 cells were detected in the livers of IL-1 alpha-treated animals 5 min after injection, and 7 times as many were found after 24 h. Intravital videomicroscopy showed marked differences in the arrest pattern of the B16F1 cells between controls and IL-1 alpha-treated mi ce. In controls, arrest occurred at a median distance of 32 mu m beyon d the sinusoidal inlet, where the median sinusoidal diameter was 16 mu m. However, in IL-1 alpha-treated mice, arrest occurred in the presin usoidal portal vein branches, which had a median diameter of 34 mu m. Maximum observed tumor cell velocities were 2-fold less in the IL-alph a-treated mice, although there was no significant difference in the fl ow rate of RBCs. To look for effects on the adhesive properties of the hepatic microvasculature, 5 X 10(4) B16F1 cells were incubated for 15 min on 5-mu m sections of liver from control and IL-1 alpha-treated m ice. Three-fold more cells adhered to sections of liver from IL-1 alph a-treated mice. This phenomenon was blocked by GRGDS peptides and by a ntibodies to E-selectin, ICAM-1, VCAM-1, and the alpha v integrin subu nit. We postulate that pre-treatment of mice with IL-1 alpha alters a number of adhesive interactions between B16F1 cells and the hepatic mi crovasculature, contributing to the site of arrest and to the subseque nt fate of the arrested cells.