Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor.

The mannose 6-phosphate/IGF-2 receptor has been proposed to be a tumor suppressor gene on the basis of loss of heterozygosity and mutations in tumors from cancer patients. To test this hypothesis, the receptor was expressed in 66cl4, a mouse mammary tumor cell line deficient in the receptor. Expression of the receptor corrected the abnormal lysosomal trafficking phenotype displayed by these cells. Receptor expression had no apparent effect on growth or invasiveness of the cells in vitro but effectively inhibited formation of mammary tumors in BALB/c mice. Analysis of cell proliferation and apoptosis in tumors indicated that the primary effect of the receptor was to inhibit cell proliferation. Proliferation indices for receptor-deficient and receptor-expressing tumors, as determined by BrdU incorporation, were 24.6 and 7.6%, respectively. No significant effect of receptor expression on apoptosis was observed. Receptor expression similarly inhibited tumor growth in BALB/c scid mice indicating that cytotoxic T cells and other components of the immune system missing in scid mice are not involved in the receptor's tumor suppressing effect. These findings establish a role for the receptor as a bona fide tumor suppressor gene and together with previous studies, suggest an important role for the receptor in human and rodent cancers.