In vitro exposure to cadmium in rat L6 myoblasts can result in both enhancement and suppression of malignant progression in vivo

Abstract

Cadmium (Cd), a carcinogenic metal in humans and rodents, has been shown to transform cells in vitro. Cd in certain instances can also be anti-carcinogenic. The effects of Cd have been studied in different mammalian cell culture systems, where it has been shown to increase expression of several proto-oncogenes. In the present study the ability of Cd to affect malignant transformation was systematically investigated in L6 cells. Cells were grown in monolayer culture with concentrations of either 0 or 0.5 microM CdCl2 in the medium. Cell cultures treated with Cd for 9 weeks showed growth of large colonies in soft agar, while untreated control cells did not. When injected s.c. into athymic nude mice the 9 week Cd-treated cells gave rise to large, highly malignant sarcomas, resulting in high host mortality (9 dead/9 injected, 100%) by 7 weeks. Mice injected with untreated control cells also developed tumors, but of significantly smaller size and growth rate and associated with a lower host mortality (4/10, 40%, P </= 0.01) by 7 weeks. Tumors resulting from untreated cells averaged approximately 50% the size (e.g. maximum diameter 12.9 mm at 23 days) of those resulting from injection of Cd-treated cells (22.2 mm at 23 days). Northern 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 strong down-regulation at 8 weeks of exposure associated with Cd-induced transformation of L6 cells. Cells exposed to high levels of Cd in vitro (1.0 microM) resulted in decreased tumor growth in vivo compared with control cells, possibly demonstrating the anti-carcinogenic capabilities 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 have both carcinogenic and anti-carcinogenic effects.