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.

  • Article
  • Published:

Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice

Nature Medicine volume 4, pages 1053–1057 (1998)Cite this article

Abstract

The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids 1 . Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development 2, 3, 4 . There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer 5, 6 . Therefore, the peroxisome proliferator-activated receptor γ (PPARγ; ref. 7 ), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon 8, 9 , may be involved in this process. Activation of PPARγ by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APC Min /+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARγ. Treatment with PPARγ agonists increased β-catenin levels both in the colon of C57BL/6J-APC Min /+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the β-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARγ activation modifies the development of colon tumors in C57BL/6J-APC Min /+ mice.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Effect of BRL-49,653 and troglitazone treatment on tumor number and size in the intestinal tract of C57BL/6J-APCMin/+ mice.
Figure 2: Expression of PPARγβ-catenin, COX-2 and β-actin in the intestinal tract of C57BL/6J-APCMin/+ mice.
Figure 3: Histological and histochemical analysis of colon tumors in C57BL/6J-APCMin/+ mice.
Figure 4: Effect of BRL-49,653 treatment on β-catenin and COX-2 expression in the colon.

Similar content being viewed by others

References

  1. Kinzler, K.W. & Vogelstein, B. Lessons from heriditary colorectal cancer. Cell 87, 159-170 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Thun, M.J., Namboodiri, M.M. & Heath, C.W. Aspirin use and reduced risk of fatal colon cancer. N. Engl. J. Med. 325, 1593-1596 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Oshima, M. et al. Suppression of intestinal polyposis in APCΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803-809 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Jacoby, R.F. et al. Chemoprevention of spontaneous intestinal adenoma in the ApcMin mouse model by the nonsteroidal anti-inflammatory drug piroxicam. Cancer Res. 56, 710-714 ( 1996).

    CAS  PubMed  Google Scholar 

  5. Giovanucci, E. & Willet, W.C. Dietary factors and risk of colon cancer. Ann. Med. 26, 443-452 (1994).

    Article  Google Scholar 

  6. Wasan, H.S., Novelli, M., Bee, J. & Bodmer, W.F. Dietary fat influences on polyp phenotype in multiple intestinal neoplasia mice. Proc. Natl. Acad. Sci. USA 94, 3308-3313 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schoonjans, K., Martin, G., Staels, B. & Auwerx, J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr. Opin. Lipidol. 8, 159-166 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Fajas, L. et al. Organization, promoter analysis and expression of the human PPARγ gene. J. Biol. Chem. 272, 18779 -18789 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Mansen, A., Guardiola-Diaz, H., Rafter, J., Branting, C. & Gustafsson, J.A. Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochem. Biophys. Res. Commun. 222, 844- 851 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Tontonoz, P., Hu, E. & Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147-1156 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Lehmann, J.M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ). J. Biol. Chem. 270, 12953-12956 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Forman, B.M. et al. 15-Deoxy-Δ12,14 prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83 , 803-812 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Kliewer, S.A. et al. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 83, 813-819 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Su, L.K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668 -670 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Nishisho, I. et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665-669 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Groden, J. et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589- 600 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Powell, S.M. et al. Molecular diagnosis of familial adenomatous polyposis. N. Engl. J. Med. 329, 1982-1987 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Miyoshi, Y. et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum. Mol. Genet. 1, 229-233 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Altiok, S., Xu, M. & Spiegelman, B. PPARγ induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev. 11, 1987-1998 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shao, D. & Lazar, M.A. Peroxisome proliferator activated receptor γ, CCAAT/enhancer binding protein α, and cell cycle status regulate the commitment to adipocyte differentiation. J. Biol. Chem. 272, 21473-21478 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  21. Tontonoz, P. et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc. Natl. Acad. Sci. USA 94, 237-241 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hunter, T. Oncoprotein networks. Cell 88, 333- 346 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Willert, K. & Nusse, R. β-catenin: a key mediator of Wnt signalling. Curr. Opin. Genet. Develop. 8, 95-102 (1998).

    Article  CAS  Google Scholar 

  24. Levy, G.D. Prostaglandin H synthethases, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB Journal 11, 234- 247 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Tsuji, M. & DuBois, R.N. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83, 493-501 (1995).

    Article  Google Scholar 

  26. Dietrich, W.F. et al. Genetic identification of Mom-1 a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75, 631-639 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. MacPhee, M. et al. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of APCMin-induced intestinal neoplasia. Cell 81, 957-966 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  28. Cormier, R.T. et al. Secretory phospholipase PLa2g2a confers resistance to intestinal tumorigenesis. Nature Genet. 17, 88- 91 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Charalambous, D. & O'Brien, P.E. Inhibition of colon cancer precursors in the rat by sulindac sulphone is not dependent on inhibition of prostaglandin synthesis. J. Gastroenterol. Hepatol. 11, 307-310 (1996 ).

    Article  CAS  PubMed  Google Scholar 

  30. Piazza, G.A. et al. Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res. 57, 2909-2915 (1997).

    CAS  PubMed  Google Scholar 

  31. Chiu, C.H., McEntee, M.F. & Whelan, J. Sulindac causes rapid regression of preexisting tumors in Min/+ mice independent of prostaglandin synthesis. Cancer Res. 57, 4267-4273 ( 1997).

    CAS  PubMed  Google Scholar 

  32. Scheppach, W. Effects of short chain fatty acids on gut morphology and function. Gut 35, S35-S38 (1994 ).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Singh, B., Halestrap, A.P. & Paraskeva, C. Butyrate can act as a stimulator growth or inducer of apoptosis in human colonic epithelial cell lines depending on the presence of alternative energy sources. Carcinogenesis 18, 1265-1270 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Holm, E. et al. Substrate balances across colonic carcinomas in humans. Cancer Res. 55, 1373-1378 ( 1995).

    CAS  PubMed  Google Scholar 

  35. Ricote, M., Li, A.C., Willson, T.M., Kelly, C.J. & Glass, C.K. The peroxisome proliferator-activated receptor γ is a negative regulator of macrophage activation. Nature 391, 79-82 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Jiang, C., Ting, A.T. & Seed, B. PPARγ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82-86 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Saez, E. et al. Activators of the nuclear receptor PPARγ enhance colon polyp formation. Nature Med. 4, 1058 -1061 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Staels, B. et al. Fibrates down-regulate apolipoprotein C-III expression independent of induction of peroxisomal Acyl Co-enzyme A Oxidase. J. Clin. Invest. 95, 705-712 ( 1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge J.-F. Colombel, R. Evans, M. Leibowitz, D. Moller, B. Paulweber, J. Olefsky, E. Saez, A. Saltiel, P. Tontonoz, and members of the Auwerx lab for discussions and suggestions. Support of grants from Association pour la Recherche contre le Cancer (ARC), from INSERM, from Institut Pasteur de Lille, and from Ligand Pharmaceuticals is acknowledged. J. A. is a research director from CNRS.

Author information

Authors and Affiliations

  1. LBRE, U.325 INSERM, Département d'Athérosclérose Institut Pasteur, 59019, Lille, France

    Anne-Marie Lefebvre, Jamila Najib, Jean-Charles Fruchart & Johan Auwerx

  2. Department of Pathology, Katholieke Universiteit, 3000, Leuven, Belgium

    Inhua Chen & Karel Geboes

  3. Clinique des maladies de l'appareil Digestif, Hopital Claude Huriez, CHU, 59037, Lille, France

    Pierre Desreumaux

  4. Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, 92121 , California, USA

    Mike Briggs & Rich Heyman

Authors
  1. Anne-Marie Lefebvre
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Inhua Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Pierre Desreumaux
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Jamila Najib
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Jean-Charles Fruchart
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Karel Geboes
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Mike Briggs
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Rich Heyman
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Johan Auwerx
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Johan Auwerx.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lefebvre, AM., Chen, I., Desreumaux, P. et al. Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 4, 1053–1057 (1998). https://doi.org/10.1038/2036

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/2036

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing