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Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation

Nature Genetics volume 40, pages 1436–1444 (2008)Cite this article

Abstract

PTEN acts as a tumor suppressor in a range of tissue types and has been implicated in the regulation of intestinal stem cells. To study Pten function in the intestine, we used various conditional transgenic strategies to specifically delete Pten from the mouse intestinal epithelium. We show that Pten loss specifically within the adult or embryonic epithelial cell population does not affect the normal architecture or homeostasis of the epithelium. However, loss of Pten in the context of Apc deficiency accelerates tumorigenesis through increased activation of Akt, leading to rapid development of adenocarcinoma. We conclude that Pten is redundant in otherwise normal intestinal epithelium and epithelial stem cells but, in the context of activated Wnt signaling, suppresses progression to adenocarcinoma through modulation of activated Akt levels.

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Figure 1: Induction with β-naphthoflavone causes recombination in the intestine, leading to loss of Pten protein from the epithelium.
Figure 2: Loss of Pten does not cause gross phenotypic changes in the small intestine.
Figure 3: Pten deletion results in increased levels of activated Akt.
Figure 4: Pten deficiency does not alter the number of crypt clonogens or β-catenin localization.
Figure 5: Loss of Pten in utero does not affect the normal development of the mouse small intestine.
Figure 6: Deficiency of both Pten and Apc leads to activation of Akt.
Figure 7: Pten deficiency causes rapid progression to adenocarcinoma, associated with increased activation of Akt.

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Acknowledgements

We thank M. Bishop, L. Pietzka and D. Scarborough for technical assistance and R. Kemp for assistance with the epithelial extraction protocol. Villin-CreERT2 mice were provided by S. Robine (Center National de la Recherche Scientifique/Institut Curie). This work was supported by Cancer Research UK and the Wales Gene Park and by grants to A.T. from the Swiss National Science Foundation, the Swiss Cancer League, the EU FP6 INTACT program and the EU FP7 program 'Eurosystem'.

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Author notes

  1. Nicole Dubois & Andreas Trumpp

    Present address: Present addresses: McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada (N.D.) and Division of Cell Biology, Deutsches Krebsforschungszentrum (DKFZ) DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany (A.T.).,

Authors and Affiliations

  1. Cardiff School of Biosciences, Cardiff University, CF10 3US, UK

    Victoria Marsh & Alan R Clarke

  2. Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK

    Douglas J Winton

  3. Wales College of Medicine, Cardiff University, CF14 4XN, UK

    Geraint T Williams

  4. Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, School of Life Science, Epalinges, CH-1066, Switzerland

    Nicole Dubois & Andreas Trumpp

  5. The Beatson Institute, Garscube Estate, Glasgow, G61 1BD, UK

    Owen J Sansom

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  1. Victoria Marsh
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Contributions

V.M., O.J.S., A.T. and A.R.C. designed this study; V.M., O.J.S., G.T.W. and N.D. did the phenotype assessment; and V.M., D.J.W., O.J.S. and A.R.C. contributed to the writing of this paper.

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Correspondence to Owen J Sansom.

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Marsh, V., Winton, D., Williams, G. et al. Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation. Nat Genet 40, 1436–1444 (2008). https://doi.org/10.1038/ng.256

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