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.

  • Letter
  • Published:

LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis

Nature Genetics volume 40, pages 455–459 (2008)Cite this article

Abstract

Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS)1 manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11+/− mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps4, raising the possibility of non-epithelial origins in tumorigenesis. Here we show that either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS. Stk11-deficient mesenchymal cells produced less TGFβ, and defective TGFβ signaling to epithelial cells coincided with epithelial proliferation. We also noted TGFβ signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS.

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: Smooth-muscle targeted inactivation of Stk11 recapitulates polyp development in Stk11+/− mice.
Figure 2: Increased myofibroblast-like (SMA+ desmin−) cells in stromal areas with Stk11 recombination.
Figure 3: Decreased TGFβ signaling and associated epithelial proliferation following stromal Stk11 deletion.
Figure 4: Human Peutz-Jeghers syndrome polyps show increased SMA-positive myogenic cells in stroma and associated decrease of TGFβ signaling.

Similar content being viewed by others

References

  1. Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391, 184–187 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Rossi, D.J. et al. Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc. Natl. Acad. Sci. USA 99, 12327–12332 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Hernan, I. et al. De novo germline mutation in the serine-threonine kinase STK11/LKB1 gene associated with Peutz-Jeghers syndrome. Clin. Genet. 66, 58–62 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Sanchez-Cespedes, M. et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659–3662 (2002).

    CAS  PubMed  Google Scholar 

  6. Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Entius, M.M. et al. Peutz-Jeghers polyps, dysplasia, and K-ras codon 12 mutations. Gut 41, 320–322 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ylikorkala, A. et al. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 293, 1323–1326 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Kuhbandner, S. et al. Temporally controlled somatic mutagenesis in smooth muscle. Genesis 28, 15–22 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Boesten, L.S. et al. Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death. Cell Death Differ. 13, 2089–2098 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Entius, M.M. et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J. Clin. Pathol. 54, 126–131 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hawley, S.A. et al. Complexes between the LKB1 tumor suppressor, STRADalpha/beta and MO25alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shaw, R.J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Owens, G.K., Kumar, M.S. & Wamhoff, B.R. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Rev. 84, 767–801 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Powell, D.W., Adegboyega, P.A., Di Mari, J.F. & Mifflin, R.C. Epithelial cells and their neighbors I. Role of intestinal myofibroblasts in development, repair, and cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G2–G7 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Hirschi, K.K., Rohovsky, S.A. & D'Amore, P.A. PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J. Cell Biol. 141, 805–814 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kuemmerle, J.F. Autocrine regulation of growth in cultured human intestinal muscle by growth factors. Gastroenterology 113, 817–824 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Kurokowa, M., Lynch, K. & Podolsky, D.K. Effects of growth factors on an intestinal epithelial cell line: transforming growth factor beta inhibits proliferation and stimulates differentiation. Biochem. Biophys. Res. Commun. 142, 775–782 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Russell, W.E., Coffey, R.J. Jr., Ouellette, A.J. & Moses, H.L. Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat. Proc. Natl. Acad. Sci. USA 85, 5126–5130 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Halttunen, T., Marttinen, A., Rantala, I., Kainulainen, H. & Maki, M. Fibroblasts and transforming growth factor beta induce organization and differentiation of T84 human epithelial cells. Gastroenterology 111, 1252–1262 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Bhowmick, N.A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Kim, B.G. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441, 1015–1019 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Haramis, A.P. et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684–1686 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Abe, M. et al. An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal. Biochem. 216, 276–284 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Masur, S.K., Dewal, H.S., Dinh, T.T., Erenburg, I. & Petridou, S. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc. Natl. Acad. Sci. USA 93, 4219–4223 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Rifkin (New York University Medical Center) and K. Koli (Haartman Institute, University of Helsinki) for reagents and advice on the TGFβ assays, and S. Räsänen, O. Kokkonen, J. Bärlund, B. Tjäder, S. Laine and K. Mänttäri for technical assistance. This work was supported by grants from the Academy of Finland, Biocentrum Helsinki, Finnish Cancer Organization, Ida Montin Foundation, Orion-Farmos Research Foundation and Sigrid Juselius Foundation. R.A.D. is an American Cancer Society Research Professor and is supported by grants from the US National Institutes of Health and the Belfer Foundation.

Author information

Authors and Affiliations

  1. Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, 00014 University of Helsinki, Finland

    Pekka Katajisto, Kari Vaahtomeri, Niklas Ekman, Eeva Ventelä, Ari Ristimäki & Tomi P Mäkelä

  2. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland

    Ari Ristimäki

  3. Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Nabeel Bardeesy

  4. Interfakultäres Institut für Biochemie, Signaltransduktion-Transgene Modelle, Universität Tübingen, Hoppe-Seyler-Str. 4, Tübingen, 72076, Germany

    Robert Feil

  5. Departments of Medical Oncology, Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science, Medicine and Genetics, Dana Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ronald A DePinho

Authors
  1. Pekka Katajisto
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Kari Vaahtomeri
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Niklas Ekman
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Eeva Ventelä
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Ari Ristimäki
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Nabeel Bardeesy
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Robert Feil
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Ronald A DePinho
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Tomi P Mäkelä
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Tomi P Mäkelä.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Figures 1–3 (PDF 800 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katajisto, P., Vaahtomeri, K., Ekman, N. et al. LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nat Genet 40, 455–459 (2008). https://doi.org/10.1038/ng.98

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.98

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