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 Vortmeyer, Wilhelm Krek

Research output: Contribution to journalArticle

33 Citations (Scopus)

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

Fingerprint

Cystadenoma
Metaplasia
Mutation
Phosphatidylinositol 3-Kinase
Neoplasms
von Hippel-Lindau Disease
Stem Cells
Epithelium
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Frew, I. J., Minola, A., Georgiev, S., Hitz, M., Moch, H., Richard, S., ... Krek, W. (2008). Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia. Molecular and Cellular Biology, 28(14), 4536-4548. https://doi.org/10.1128/MCB.02132-07

Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia. / Frew, Ian J.; Minola, Andrea; Georgiev, Strahil; Hitz, Manuela; Moch, Holger; Richard, Stéphane; Vortmeyer, Alexander; Krek, Wilhelm.

In: Molecular and Cellular Biology, Vol. 28, No. 14, 01.07.2008, p. 4536-4548.

Research output: Contribution to journalArticle

Frew, IJ, Minola, A, Georgiev, S, Hitz, M, Moch, H, Richard, S, Vortmeyer, A & Krek, W 2008, 'Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia', Molecular and Cellular Biology, vol. 28, no. 14, pp. 4536-4548. https://doi.org/10.1128/MCB.02132-07
Frew, Ian J. ; Minola, Andrea ; Georgiev, Strahil ; Hitz, Manuela ; Moch, Holger ; Richard, Stéphane ; Vortmeyer, Alexander ; Krek, Wilhelm. / Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 14. pp. 4536-4548.
@article{360895653e39486e886633924b45a17c,
title = "Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia",
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.",
author = "Frew, {Ian J.} and Andrea Minola and Strahil Georgiev and Manuela Hitz and Holger Moch and St{\'e}phane Richard and Alexander Vortmeyer and Wilhelm Krek",
year = "2008",
month = "7",
day = "1",
doi = "10.1128/MCB.02132-07",
language = "English (US)",
volume = "28",
pages = "4536--4548",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "14",

}

TY - JOUR

T1 - Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia

AU - Frew, Ian J.

AU - Minola, Andrea

AU - Georgiev, Strahil

AU - Hitz, Manuela

AU - Moch, Holger

AU - Richard, Stéphane

AU - Vortmeyer, Alexander

AU - Krek, Wilhelm

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=47049111684&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=47049111684&partnerID=8YFLogxK

U2 - 10.1128/MCB.02132-07

DO - 10.1128/MCB.02132-07

M3 - Article

C2 - 18474617

AN - SCOPUS:47049111684

VL - 28

SP - 4536

EP - 4548

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 14

ER -