Combined VHLH and PTEN mutation causes genital tract cystadenoma and squamous metaplasia.
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 HIF1alpha and HIF2alpha, 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.
Frew
Ian J
IJ
Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.
Minola
Andrea
A
Georgiev
Strahil
S
Hitz
Manuela
M
Moch
Holger
H
Richard
Stéphane
S
Vortmeyer
Alexander O
AO
Krek
Wilhelm
W
D000818:Animals; D003537:Cystadenoma / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005835:Genitalia / Q000166:cytology / Q000473:pathology; D006801:Humans; D008297:Male; D008679:Metaplasia / Q000235:genetics; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism; D013088:Spermatocele / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics
D051880:Receptors, Notch; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; C497446:VHL protein, human; C494469:VHL protein, mouse