Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Arends MJ, Morris RG and Wyllie AH . (1990). Am. J. Pathol., 136, 593–608.

  • Aslakson CJ and Miller FR . (1992). Cancer Res., 52, 1399–1405.

  • Beck S, Sakurai T, Eustace BK, Beste G, Schier R, Rudert F and Jay DG . (2002). Proteomics, 2, 247–255.

  • Braulke T, Causin C, Waheed A, Junghans U, Hasilik A, Maly P, Humbel RE and Figura von K . (1988). Biochem. Biophys. Res. Commun., 150, 1287–1293.

  • Caligo MA, Ghimenti C, Sensi E, Marchetti A, Bertacca G, Giulianotti PG, Fornaciari G and Bevilacqua G . (2000). Oncol. Rep., 7, 1371–1375.

  • Calin GA, Gafa R, Tibiletti MG, Herlea V, Becheanu G, Cavazzini L, Barbanti-Brodano G, Nenci I, Negrini M and Lanza G . (2000). Int. J. Cancer, 89, 230–235.

  • Cattoretti G, Pileri S, Parravicini C, Becker MH, Poggi S, Bifulco C, Key G, D'Amato L, Sabattini E and Feudale E . (1993). J. Pathol., 171, 83–98.

  • Chen Z, Ge Y, Landman N and Kang JX . (2002). BMC Cancer, 2, 18.

  • Cuozzo JW, Tao K, Cygler M, Mort JS and Sahagian GG . (1998). J. Biol. Chem., 273, 21067–21076.

  • Cuozzo JW, Tao K, Wu QL, Young W and Sahagian GG . (1995). J. Biol. Chem., 270, 15611–15619.

  • Dennis PA and Rifkin DB . (1991). Proc. Natl. Acad. Sci. USA, 88, 580–584.

  • Dole M, Nunez G, Merchant AK, Maybaum J, Rode CK, Bloch CA and Castle VP . (1994). Cancer Res., 54, 3253–3259.

  • Filson AJ, Louvi A, Efstratiadis A and Robertson EJ . (1993). Development, 118, 731–736.

  • Gavrieli Y, Sherman Y and Ben-Sasson SA . (1992). J. Cell. Biol., 119, 493–501.

  • Gemma A, Hosoya Y, Uematsu K, Seike M, Kurimoto F, Yoshimura A, Shibuya M and Kudoh S . (2000). Lung Cancer, 30, 91–98.

  • Ghahary A, Tredget EE and Shen Q . (1999). J. Cell. Physiol., 180, 61–70.

  • Godar S, Horejsi V, Weidle UH, Binder BR, Hansmann C and Stockinger H . (1999). Eur. J. Immunol., 29, 1004–1013.

  • Hale AJ, Smith CA, Sutherland LC, Stoneman VE, Longthorne V, Culhane AC and Williams GT . (1996). Eur. J. Biochem., 237, 884.

  • Hankins GR, De Souza AT, Bentley RC, Patel MR, Marks JR, Iglehart JD and Jirtle RL . (1996). Oncogene, 12, 2003–2009.

  • Ikezu T, Okamoto T, Giambarella U, Yokota T and Nishimoto I . (1995). J. Biol. Chem., 270, 29224–29228.

  • Jamieson TA, Brizel DM, Killian JK, Oka Y, Jang HS, Fu X, Clough RW, Vollmer RT, Anscher MS and Jirtle RL . (2003). BMC Cancer, 3, 4.

  • Kang JX, Bell J, Beard RL and Chandraratna RA . (1999). Cell. Growth Differ., 10, 591–600.

  • Kang JX, Li Y and Leaf A . (1997). Proc. Natl. Acad. Sci. USA, 94, 13671–13676.

  • Kiess W, Blickenstaff GD, Sklar MM, Thomas CL, Nissley SP and Sahagian GG . (1988). J. Biol. Chem., 263, 9339–9344.

  • Kong FM, Anscher MS, Washington MK, Killian JK and Jirtle RL . (2000). Oncogene, 19, 1572–1578.

  • Lau MM, Stewart CE, Liu Z, Bhatt H, Rotwein P and Stewart CL . (1994). Genes Dev., 8, 2953–2963.

  • Leboulleux S, Gaston V, Boulle N, Le Bouc Y and Gicquel C . (2001). Eur. J. Endocrinol., 144, 163–168.

  • Lee JS, Weiss J, Martin JL and Scott CD . (2003). Int. J. Cancer, 107, 564–570.

  • Lobel P, Dahms NM, Breitmeyer J, Chirgwin JM and Kornfeld S . (1987). Proc. Natl. Acad. Sci. USA, 84, 7523.

  • MacDonald RG, Pfeffer SR, Coussens L, Tepper MA, Brocklebank CM, Mole JE, Anderson JK, Chen E, Czech MP and Ullrich A . (1988). Science, 239, 1134–1137.

  • McKinnon T, Chakraborty C, Gleeson LM, Chidiac P and Lala PK . (2001). J. Clin. Endocrinol. Metab., 86, 3665–3674.

  • Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA and Rutter WJ . (1987). Nature, 329, 301–307.

  • Motyka B, Korbutt G, Pinkoski MJ, Heibein JA, Caputo A, Hobman M, Barry M, Shostak I, Sawchuk T, Holmes CF, Gaulide J and Bleackley RC . (2000). Cell, 103, 491–500.

  • Nykjaer A, Christensen EI, Vorum H, Hager H, Petersen CM, Roigaard H, Min HY, Vilhardt F, Moller LB, Kornfeld S and Gliemann J . (1998). J. Cell. Biol., 141, 815–828.

  • O'Gorman DB, Costello M, Weiss J, Firth SM and Scott CD . (1999). Cancer Res., 59, 5692–5694.

  • O'Gorman DB, Weiss J, Hettiaratchi A, Firth SM and Scott CD . (2002). Endocrinology, 143, 4287–4294.

  • Oka Y, Waterland RA, Killian JK, Nolan CM, Jang HS, Tohara K, Sakaguchi S, Yao T, Iwashita A, Yata Y, Takahara T, Sato S, Suzuki K, Masuda T and Jirtle RL . (2002). Hepatology, 35, 1153–1163.

  • Okamoto T, Katada T, Murayama Y, Ui M, Ogata E and Nishimoto I . (1990). Cell, 62, 709–717.

  • Sahagian GG, Distler J and Jourdian GW . (1981). Proc. Natl. Acad. Sci. USA, 78, 4289–4293.

  • Seitz S, Wassmuth P, Plaschke J, Schackert HK, Karsten U, Santibanez-Koref MF, Schlag PM and Scherneck S . (2003). Genes Chromosomes Cancer, 37, 29–35.

  • Souza RF, Wang S, Thakar M, Smolinski KN, Yin J, Zou TT, Kong D, Abraham JM, Toretsky JA and Meltzer SJ . (1999). Oncogene, 18, 4063–4068.

  • Tao K, Li J, Warner J, MacLeod K, Miller FR and Sahagian GG . (2001). Int. J. Oncol., 19, 1333–1339.

  • Tong PY, Tollefsen SE and Kornfeld S . (1988). J. Biol. Chem., 263, 2585–2588.

  • Wang S, Souza RF, Kong, D, Yin J, Smolinski KN, Zou TT, Frank T, Young J, Flanders KC, Sugimura H, Abraham JM and Meltzer SJ . (1997). Cancer Res., 57, 2543–2546.

  • Wang ZQ, Fung MR, Barlow DP and Wagner EF . (1994). Nature, 372, 464–467.

  • Yamada T, De Souza AT, Finkelstein S and Jirtle RL . (1997). Proc. Natl. Acad. Sci. USA, 94, 10351–10355.

  • Zavras AI, Pitiphat W, Wu T, Cartsos V, Lam A, Douglass CW and Diehl SR . (2003). Cancer Res., 63, 296–297.

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G Gary Sahagian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208039

Keywords

This article is cited by

Search

Quick links