Study of the inhibitory effects on invasion and metastasis of human squamous cell carcinoma by intensifying endothelial cell to cell adhesion

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Diisoprppyl,1,3-dithiol-2-y1idenemalonate(MT) is clinically used as a hepatoprotective agent. Because we noticed that the differentiation of cultured vascular endothelial cell, we have examined its effects on lung metastasis of the highly metastatic rat mammary carcinoma c-SST-2. MT was orally administered to syngenic SHR rats from 7 days before or after s. c.. inoculation of c-SST-2 cells to the end of the experiments. In the MT treated rats, pulumonary metastasis was markedly suppressed compared with the non-treated rats. In- the rats treated with MT for 19 days after i. v. inoculation of c-SST-2 cells, lung metastasis was also significantly suppressed. An in vitro invasion assay using a rat lung endothelial cell (RLE) monolayer revealed that pretreatment of the RLE with MT, but not c-SST-2 cells, significantly reduced the invasion of the RLE monolayer by c-SST-2 cells. An in vitro vascular permeability assay demonstrated that MT prevented the increase in permeability of the RLE monolayer by serum starvation. On the other hand, in vivo and in vitro growth, gelatinase production and adhesion to the RLE monolayer of c-SST-2 cells were not affected by NT treatment. Electronmicroscopical examination of the RLE monolayer treated with MT showed the development of gap junction Structure. A junction associated protein, cnnexin43 was also elevated at RLE treated with MT. These findings suggests that MT suppressed tumor metastasis by intensifying the cell-cell contact of endothelial cell, thus preventing tumor cells from invading vascular endothelium.