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Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor
1Department of Physiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Abstract:
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.
Insights
The mannose 6-phosphate/IGF-2 receptor acts as a tumor suppressor by inhibiting cancer cell proliferation, not affecting apoptosis. This finding supports its role in both human and rodent cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The mannose 6-phosphate/IGF-2 receptor (M6P/IGF2R) is implicated as a tumor suppressor due to observed mutations in human cancers.
- Previous studies suggest M6P/IGF2R's potential role in tumorigenesis, but direct functional evidence was lacking.
Purpose of the Study:
- To investigate the tumor suppressor function of the M6P/IGF2R.
- To determine the mechanism by which M6P/IGF2R influences tumor development.
Main Methods:
- M6P/IGF2R was expressed in a mouse mammary tumor cell line (66cl4) deficient in the receptor.
- Tumorigenesis was assessed in vivo using BALB/c and BALB/c scid mice.
- Cell proliferation and apoptosis were analyzed in tumors using BrdU incorporation.
Main Results:
- Receptor expression corrected lysosomal trafficking defects in 66cl4 cells.
- In vivo, M6P/IGF2R expression significantly inhibited mammary tumor formation without affecting cell growth or invasiveness in vitro.
- Tumor growth inhibition was attributed to reduced cell proliferation (24.6% to 7.6% proliferation index) rather than altered apoptosis.
Conclusions:
- M6P/IGF2R functions as a bona fide tumor suppressor gene.
- The tumor-suppressive effect is mediated by inhibiting cell proliferation, independent of immune system involvement.
- These findings highlight the M6P/IGF2R's critical role in preventing mammary tumor development and suggest its significance in human and rodent cancers.
