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Molecular and Cellular Biology, July 2008, p. 4536-4548, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.02132-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Combined Vhlh and Pten Mutation Causes Genital Tract Cystadenoma and Squamous Metaplasia{triangledown}

Ian J. Frew,1 Andrea Minola,1 Strahil Georgiev,1 Manuela Hitz,1 Holger Moch,2 Stéphane Richard,3 Alexander O. Vortmeyer,4 and Wilhelm Krek1*

Institute of Cell Biology, ETH Zurich, Zurich, Switzerland,1 Institute of Surgical Pathology, Department of Pathology, University Hospital Zurich, Zurich, Switzerland,2 Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, and CNRS FRE-2939, Institute de Cancerologie Gustave Roussy, Villejuif, France,3 Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, Maryland4

Received 30 November 2007/ Returned for modification 28 January 2008/ Accepted 30 April 2008

Patients with von Hippel-Lindau (VHL) disease develop tumors in a range of tissues, but existing mouse models of Vhlh mutation have failed to reproduce these lesions. Epididymal cystadenomas arise frequently in VHL patients, but VHL mutation alone is believed to be insufficient for tumor formation, implying a requirement for cooperating mutations in epididymal pathogenesis. Here we show that epididymal cystadenomas from VHL patients frequently also lack expression of the PTEN tumor suppressor and display activation of phosphatidylinositol 3-kinase (PI3K) pathway signaling. Strikingly, while conditional inactivation of either Vhlh or Pten in epithelia of the mouse genital tract fails to produce a tumor phenotype, their combined deletion causes benign genital tract tumors with regions of squamous metaplasia and cystadenoma. The latter are histologically identical to lesions found in VHL patients. Importantly, these lesions are characterized by expansion of basal stem cells, high levels of expression and activity of HIF1{alpha} and HIF2{alpha}, and dysregulation of PI3K signaling. Our studies suggest a model for cooperative tumor suppression in which inactivation of PTEN facilitates epididymal cystadenoma genesis initiated by loss of VHL.

* Corresponding author. Mailing address: Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland. Phone: 41 44 633 3447. Fax: 41 44 633 13 57. E-mail: wilhelm.krek{at}cell.biol.ethz.ch

{triangledown} Published ahead of print on 12 May 2008.

Molecular and Cellular Biology, July 2008, p. 4536-4548, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.02132-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Frew, I. J., Krek, W. (2008). pVHL: A Multipurpose Adaptor Protein. Sci Signal 1: pe30-pe30 [Abstract] [Full Text]  


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