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

Oncogene volume 23, pages 9359–9368 (2004)Cite this article

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.

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Acknowledgements

We thank Dr Peter Lobel (Robert Wood Johnson School of Medicine) for the psFFVneo and psFFVneo-m6PR expression vectors and Drs Brent Cochran, James Dice, and Michael Forgac (Tufts University School of Medicine) for critical review of the manuscript. We also acknowledge the excellent support and assistance of Mr David Panzarella and Mr William Anderson at Xenogen Corporation in setting up the Xenogen Imager in the laboratory and training coworkers in its use and thank Dr Kun Ru (Tufts-New England Medical Center, Boston, USA) for help with immunohistochemistry. This work was supported by Grant RO1-CA66575 from the National Cancer Institute, Grant P3ODK34928 from NIDDK, and by PhD Dissertation Fellowship #01-875 from the Komen Breast Cancer Foundation.

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  1. Department of Physiology, Tufts University School of Medicine, Boston, 02111, MA, USA

    Jin Li & G Gary Sahagian

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  1. Jin Li
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Correspondence to G Gary Sahagian.

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Li, J., Sahagian, G. Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor. Oncogene 23, 9359–9368 (2004). https://doi.org/10.1038/sj.onc.1208039

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