OVEREXPRESSION OF METALLOPROTEINASE INHIBITOR IN B16F1O CELLS DOES NOT AFFECT EXTRAVASATION BUT REDUCES TUMOR-GROWTH

It is widely accepted that a major role of matrix metalloproteinases i n the metastatic process is degradation of basement membrane during ca ncer cell invasion. We tested the hypothesis that the reduction in met astatic potential which has been demonstrated for B16F10 melanoma cell s genetically engineered to overexpress tissue inhibitor of metallopro teinase-l (TIMP-1) is caused by a decrease in their ability to extrava sate. Using intravital videomicroscopy of chick embryo chorioallantoic membrane, we studied extravasation of B16F10 cells and B16F10 cells t ransfected to overexpress TIMP-1. More than 800 cells in 36 chick embr yos were analyzed for each cell line during 72 h postinjection. TIMP-1 upregulation had no effect on the time course of extravasation, virtu ally all cells from both cell lines having extravasated by 36 h. We al so studied the morphology of micrometastases at days 3 and 7. Lack of contact between cancer cells within micrometastases at day 3 and reduc tion in size and number of tumors at day 7 were observed for TIMP-1 ov erexpressor cells compared to B16F10. Our findings illustrate that the imbalance between TIMP and metalloproteinases created by overexpressi on of TIMP-1 in B16F10 cells reduces their metastatic ability in vivo by affecting tumor growth postextravasation.