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.

  • Short Communication
  • Published:

Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice

Abstract

Epidemiological evidence indicates a link between obesity and human colon cancer. A putative association between obesity and colon tumorigenesis has been explored experimentally using chemical carcinogens administered to obese rodents. The main objective of this study was to generate a new mouse line that displays both obesity and intestinal tumorigenesis. To this end, we have generated C57BLKS-mLeprdb/db; Apc1638N/+ mice combining both db and Apc mutations. The db mutation results in obesity and type 2 diabetes, the Apc mutation is a key initiating event of intestinal neoplasia. All mice were euthanized at 6 months of age and all regions of the gastrointestinal tract examined for tumors. The results show that the combination of Apc1638N/+ and db mutations not only enhanced mutant Apc-driven small intestinal tumorigenesis but also induced gastric and colonic tumors. Homozygous db mice did not develop gastrointestinal neoplasia. These findings indicate that obesity associated with type 2 diabetes promotes gastrointestinal tumorigenesis in Apc-deficient mice and provides evidence of a mechanistic link between obesity and colorectal neoplasia.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Calle EE, Kaaks R . Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev Cancer 2004; 4: 579–591.

    Article  CAS  Google Scholar 

  2. Gunter MJ, Leitzmann MF . Obesity and colorectal cancer: epidemiology, mechanisms and candidate genes. J Nutr Bioch 2006; 17: 145–156.

    Article  CAS  Google Scholar 

  3. Giovannucci E, Michaud D . The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 2007; 132: 2208–2225.

    Article  CAS  Google Scholar 

  4. Weber RV, Stein DE, Scholes J, Kral JG . Obesity potentiates AOM-induced colon cancer. Dig Dis Sci 2000; 45: 890–895.

    Article  CAS  Google Scholar 

  5. Drew JE, Farquharson AJ, Padidar S, Duthie GG, Mercer JG, Artur JR et al. Insulin, leptin and adiponectin receptors in colon: regulation relative to differing body adiposity independent of diet and in response to dimethylhydrazine. Am J Physiol Gastrointest Liver Physiol 2007; 293: G682–G691.

    Article  CAS  Google Scholar 

  6. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996; 379: 632–635.

    Article  CAS  Google Scholar 

  7. Hummel KP, Dickie MM, Coleman DL . Diabetes, a new mutation in the mouse. Science 1966; 153: 1127–1128.

    Article  CAS  Google Scholar 

  8. Fodde R, Edelmann W, Yang K, Van Leeuwen C, Carlson C, Renault B et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumours. Proc Natl Acad Sci USA 1994; 91: 8969–8973.

    Article  CAS  Google Scholar 

  9. Yang K, Edelmann W, Fan K, Lau K, Kolli VR, Fodde R et al. A mouse model of human familial adenomatous polyposis. J Exp Zool 1997; 277: 245–254.

    Article  CAS  Google Scholar 

  10. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992; 359: 235–237.

    Article  CAS  Google Scholar 

  11. Boivin GP, Washington K, Yang K, Ward JM, Pretlow TP, Russel R et al. Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 2003; 124: 762–777.

    Article  Google Scholar 

  12. Garofalo C, Surmacz E . Leptin and Cancer. J Cell Physiol 2006; 207: 12–22.

    Article  CAS  Google Scholar 

  13. Fenton JI, Lavigne JA, Perkins SN, Liu H, Chandramoili GVR, Shih JH et al. Microarray analysis reveals that leptin induces autocrine/paracrine cascades to promote survival and proliferation of colon epithelial cells in an Apc genotype dependent fashion. Mol Carcinog 2008; 47: 9–21.

    Article  CAS  Google Scholar 

  14. Hirose Y, Hata K, Kuno T, Yoshida K, Sakata K, Yamada Y et al. Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Carcinogenesis 2004; 25: 821–825.

    Article  CAS  Google Scholar 

  15. Ealey KN, Lu S, Archer MC . Development of aberrant crypt foci in the colons of ob/ob and db/db mice: evidence that leptin is not a promoter. Mol Carcinog 2008; 47: 667–677.

    Article  CAS  Google Scholar 

  16. Stattin P, Lukanova A, Biessy C, Sodemberg S, Palmqvist R, Kaas R et al. Obesity and colon cancer: does leptin provide a link? Int J Cancer 2004; 109: 149–152.

    Article  CAS  Google Scholar 

  17. Slattery MI, Wolff RK . Leptin and colon cancer: an undefined link. Nature Clin Pract Gastroenterol & Hepatology 2007; 4: 118–119.

    Article  Google Scholar 

  18. Tilg H, Moschen AR . Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Rev Immunol 2006; 6: 772–783.

    Article  CAS  Google Scholar 

  19. Itzkowitz SH, Yio X . Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Liver Physiol 2004; 287: G1–G17.

    Google Scholar 

  20. Hursting SD, Lashinger LM, Colbert LH, Rogers CJ, Wheatley KW, Nunez NP et al. Energy balance and carcinogenesis: underlying pathways and targets for intervention. Curr Cancer Drug Targets 2007; 7: 484–491.

    Article  CAS  Google Scholar 

  21. Coleman DL . Increased metabolic efficiency in obese mutant mice. Int J Obes 1985; 9 (Suppl 2): 69–73.

    PubMed  Google Scholar 

  22. Mai V, Colbert LH, Berrigan D, Perkins SN, Pfeiffer R, Lavigne JA et al. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in ApcMin mice through different mechanisms. Cancer Res 2003; 63: 1752–1755.

    CAS  PubMed  Google Scholar 

  23. Patel AC, Nunez NP, Perkins SN, Barrett JC, Hursting SD . Effects of energy balance on cancer in genetically altered mice. J Nutr 2004; 134 (Suppl 12): 3394S–3398S.

    Article  CAS  Google Scholar 

  24. Martinez-Hernandez A, Enriques L, Moreno-Moreno MJ, Marti A . Genetics of obesity. Public Health Nutr 2007; 10: 1138–1144.

    Article  Google Scholar 

  25. Moore T, Beltran L, Carbajal S, Strom S, Traag J, Hursting SD et al. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res 2008; 1: 65–76.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from National Institutes of Health, (Postdoctoral Fellowship R25 to C Gravaghi, #CA-84301 to R Kucherlapati); National Cancer Institute (#RO1 CA76329 and #U54 CA100926 to W Edelmann) and a grant from The Irving Weinstein Foundation, Inc. USA (SA Lamprecht). We thank Dr K Zhou (Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, NY, USA) for statistical advice, M Peppas (Strang Cancer Research Laboratory, NY) for assistance in animal care and maintenance and Dr G Benigno (LSE, London School of Economics, London, UK) for revising the figures. We have no competing financial interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S A Lamprecht.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gravaghi, C., Bo, J., LaPerle, K. et al. Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice. Int J Obes 32, 1716–1719 (2008). https://doi.org/10.1038/ijo.2008.149

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2008.149

Keywords

This article is cited by

Search

Quick links