Invasive and metastatic potential induced by ras-transfection into mouse BW5147 T-lymphoma cells

Noninvasive, nonmetastatic BW5147 T-lymphoma cells were transfected with the activated human c-Ha-ras oncogene and were examined subsequently for the acquisition of invasive properties in vitro and of metastatic potential in vivo. It was found that several transfectants harboring the ras gene had become invasive in vitro, as assessed in hepatocyte cultures, and metastatic after tail vein injection into syngeneic AKR mice. The induced level of both invasive and metastatic potential appeared to depend on the level of expression of the transfected ras gene. Those transfectants exhibiting an elevated level of ras expression, mostly cells containing a high copy number of the ras gene, showed the highest invasiveness (up to 30-fold increase) and produced widespread metastasis in all mice tested. Transfectants with a low level of ras expression were less invasive and formed metastases in a few mice only, limited to a few organs or even to a single deposit in one organ. Untransfected BW cells, control transfected cells without the ras gene, and ras transfectants that did not express the gene were noninvasive and nonmetastatic. No changes in number of ras gene copies were found between isolated metastases and the transfectants from which they were derived. However, RNA analysis of the cells from the isolated metastases revealed similar, as well as elevated or diminished levels of ras transcription when compared to the corresponding cell lines prior to injection, suggesting that a persistent high expression of the ras gene is not necessarily needed for the independent growth at the secondary site. Our results indicate that the activated human ras oncogene may confer metastatic potential onto lymphoid tumor cells, probably due to the induction of invasiveness.