IN-VITRO EXPOSURE TO CADMIUM IN RAT L6 MYOBLASTS CAN RESULT IN BOTH ENHANCEMENT AND SUPPRESSION OF MALIGNANT PROGRESSION IN-VIVO

Cadmium (Cd), a carcinogenic metal in humans and rodents, has been sho wn to transform cells in vitro. Cd in certain instances can also be an ti-carcinogenic. The effects of Cd have been studied in different mamm alian cell culture systems, where it has been shown to increase expres sion of several proto-oncogenes. In the present study the ability of C d to affect malignant transformation was systematically investigated i n L6 cells. Cells were grown in monolayer culture with concentrations of either 0 or 0.5 mu M CdCl2 in the medium. Cell cultures treated wit h Cd for 9 weeks showed growth of large colonies in soft agar, while u ntreated control cells did not. When injected s.c. into athymic nude m ice the 9 week Cd-treated cells gave rise to large, highly malignant s arcomas, resulting in high host mortality (9 dead/9 injected, 100%) by 7 weeks. Mice injected with untreated control cells also developed tu mors, but of significantly smaller size and growth rate and associated with a lower host mortality (4/10, 40%, P less than or equal to 0.01) by 7 weeks. Tumors resulting from untreated cells averaged similar to 50% the size (e.g. maximum diameter 12.9 mm at 23 days) of those resu lting from injection of Cd-treated cells (22.2 mm at 23 days). Norther n blot RNA analysis indicated that although there was an increase in c -myc and c-jun expression after 2 weeks of Cd exposure, there was stro ng down-regulation at 8 weeks of exposure associated with Cd-induced t ransformation of L6 cells. Cells exposed to high levels of Cd in vitro (1.0 mu M) resulted in decreased tumor growth in vivo compared with c ontrol cells, possibly demonstrating the anti-carcinogenic capabilitie s of Cd. Thus cells exposed to low levels of Cd in vitro showed a very rapid malignant progression in vivo, while higher Cd levels in vitro suppressed in vivo tumor growth, reinforcing the concept that Cd can h ave both carcinogenic and anti-carcinogenic effects.