MMP-2 EXPRESSION IS ASSOCIATED WITH, BUT NOT SUFFICIENT FOR, MALIGNANT CONVERSION OF MURINE LTA CELLS

We previously showed that tumorigenic, non-metastatic LTA cells can be converted to a metastatic phenotype either by cell fusion with non-ma lignant NIH 3T3 cells, or by transfection with genomic DNA fr om metas tatic murine B16F1 or human IGR37 melanoma cells. In order to identify a gene present in NIH 3T3 cells that is responsible for this conversi on, we transferred DNA from an NIH 3T3 genomic library into LTA cells and tested for changes in metastatic properties, assessed in the chick embryo. We found that 3 of 4 pools of transfectant clones showed sign ificantly increased metastatic ability over the vector-only control tr ansfectants. All three metastatic transfectant pools showed significan tly increased RNA levels of the 72 kDa type IV gelatinase (MMP-2). To test whether increased expression of MMP-2 was sufficient to convert L TA cells to metastatic ability we transfected full length MMP-2 cDNA, in a CMV-promoter expression construct, into LTA cells. Stable transfe ctants with elevated MMP-2 RNA and enzymatic activity were obtained. T he highest MMP-2 expressing clone was assayed for experimental metasta tic ability in the chick embryo, and found to be no more metastatic th an LTA parental cells. We conclude that increased MMP-2 expression acc ompanies the malignant conversion of LTA cells, but MMP-2 expression a lone is not sufficient to bring about this change. The inability of LT A cells to metastasize thus appears to be due to a more complex defect than insufficient MMP-2. This study supports the idea that malignant conversion may require the concerted activation of multiple genes, whi ch are in turn controlled by regulatory genes, whose identification wi ll be important in understanding and controlling metastasis.