EFFECTS OF THE DISINTEGRIN ERISTOSTATIN ON INDIVIDUAL STEPS OF HEMATOGENOUS METASTASIS

Adhesion molecules, including integrins, are important for interaction s of cancer cells with vessel walls, a step leading to cancer metastas is. Disintegrins block the action of integrins by binding to them. We tested the hypothesis that the disintegrin eristostatin would block me tastasis by interfering with cancer cell adhesion to vessel walls, thu s preventing extravasation. Experimental metastasis assays, in which B 16F1 melanoma cells (controls vs eristostatin-treated, 25 mu g/ml) wer e injected via mesenteric veins of anesthetized C57BL/6 mice, showed t hat eristostatin reduced (P < 0.05) the mean number of liver metastase s from 14.4 to 0.6 at 11 days postinjection (p.i.). We examined three different steps in metastasis at which eristostatin could have exerted its effect, namely, cell arrest, extravasation, and migration. Contro l and eristostatin-treated B16F1. cells were fluorescently labeled and examined by videomicroscopy in liver microcirculation in vivo at vari ous times up to 14 days p.i. Measurements of vessel size in which cell arrest occurred and length/width ratio of arrested cells showed only small differences between control and eristostatin-treated cells. Eris tostatin treatment did not prevent extravasation, and the timing and p rocess of extravasation were similar for both treated and control cell s; by 34 days p.i. more than 90% of the cells had extravasated or were in the process. Eristostatin also did not affect the ability of extra vasated cells to migrate through the extracellular matrix to the subca psular region where tumors later form. Therefore, we conclude that eri stostatin exerted its primary effect by regulating the number of indiv idual cancer cells that grow after extravasation. (C) 1995 Academic Pr ess, Inc.