The IGF-II/mannose-6 phosphate receptor (IGF-II/M6PR) interacts with multiple tumor growth factors, including IGF-II and latent TGFbeta1. The IGF-II/M6PR has been proposed to be a tumor growth suppressor, a hypothesis supported by our previous finding that decreased IGF-II/M6PR expression enhances tumor growth. In this study, we further demonstrate that IGF-II/M6PR overexpression, resulting from cDNA transfection of JEG-3 choriocarcinoma cells, leads to a decreased cellular growth rate in vitro and decreased tumor growth in nude mice. Examination of several IGF-II/M6PR ligands in receptor-overexpressing cells showed no change in endogenous IGF-II or secretion of procathepsins D and L but an increase in latent TGFbeta1 secretion and activation. Cells transfected with cDNA for a truncated, soluble form of the receptor, previously shown to inhibit IGF-II-stimulated DNA synthesis, displayed a very slow growth rate in vitro and in nude mice but showed no alteration in TGFbeta1 levels. This suggests that, in IGFII/M6PR-transfected cells, increased levels of soluble IGF-II/M6PR may play a role in growth inhibition. Overall, the findings in this study are consistent with the hypothesis that the IGF-II/M6PR suppresses tumor growth.