INDUCTION OF ENDOTHELIAL-CELL APOPTOSIS BY SOLID TUMOR-CELLS

The mechanisms by which tumor cells extravasate to form metastasis rem ain controversial. Previous studies performed in vivo and in vitro dem onstrate that the contact between tumor cells and the vascular wall im pairs endothelium integrity. Here, we investigated the effect of breas t adenocarcinoma MCF-7 cells on the apoptosis of human umbilical vein endothelial cells (HUVEC). TUNEL labeling, nuclear morphology, and DNA electrophoresis indicated that MCF-7 cells induced a two-to fourfold increase in HUVEC apoptosis. Caspase-3 activity was significantly enha nced. Neither normal cells tested (mammary epithelial cells, fibroblas ts, leukocytes) nor transformed hematopoietic cells tested (HL60, Jurk at) induced HUVEC apoptosis. On the contrary, cells derived from solid tumors (breast adenocarcinoma, MDA-MB-231 and T47D; fibrosarcoma, HT 1080) had an effect similar to that of MCF-7 cells. The induction of a poptosis requires cell-to-cell contact, since it could not be reproduc ed by media conditioned by MCF-7 cells cultured alone or cocultured wi th HUVEC. Our results suggest that cells derived from solid tumors may alter the endothelium integrity by inducing endothelial cell apoptosi s. On the contrary, normal or malignant leukocytes appear to extravasa te by distinct mechanisms and do not damage the endothelium. Our data may lead to a better understanding of the steps involved in tumor cell extravasation. (C) 1998 Academic Press.