Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia

Ian J. Frew, Andrea Minola, Strahil Georgiev, Manuela Hitz, Holger Moch, Stéphane Richard, Alexander O. Vortmeyer, Wilhelm Krek

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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 HIF1α and HIF2a, 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.

Original languageEnglish (US)
Pages (from-to)4536-4548
Number of pages13
JournalMolecular and cellular biology
Volume28
Issue number14
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia'. Together they form a unique fingerprint.

  • Cite this