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 HIF2α, 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.
ACKNOWLEDGMENTS
We thank members of our laboratory for discussions. We are grateful to Peter Igarashi, Andreas Trumpp, Sabine Werner, Jan Zevada, and Patrick Pollard for providing mice and reagents, to Vincent Molonié, Sophie Ferlicot, and Marie-Christine Rousselet for providing pathological specimens, to Matteo Montani for pathological diagnosis, and to Claudio Thoma for discussions and comments on the manuscript.
This work was supported by grants to W.K. from the Josef Steiner Foundation and the Swiss National Science Foundation.