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Insulin-Like Growth Factor-II/Mannose 6-Phosphate Receptor Overexpression Reduces Growth of Choriocarcinoma Cells in Vitro and in Vivo

Kolling Institute of Medical Research, University of Sydney and Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Dr. Carolyn Scott, Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Highway, St. Leonards, New South Wales 2065, Australia. E-mail: cscott{at}med.usyd.edu.au.

The IGF-II/mannose-6 phosphate receptor (IGF-II/M6PR) interacts with multiple tumor growth factors, including IGF-II and latent TGFß1. 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 TGFß1 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 TGFß1 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.

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