Mutations in the von Hippel-Lindau tumor suppressor gene (VHL) predispose patients to develop both renal cysts and clear cell renal cell carcinoma, albeit with relatively low frequency, a finding that has been recapitulated in mice mutant for the Vhlh gene. This has led to the view that additional mutations are required to cause progression to cysts or carcinoma in VHL disease. Work in the lab of Wilhelm Krek and colleagues at ETH Zurich shows that cysts from patients with VHL disease exhibit increased activation of phosphoinositide 3-kinase (PI3K). Because the Pten tumor suppressor normally antagonizes PI3K signaling, they combined conditional inactivation of both the Vhlh and Pten tumor suppressor gene in the mouse kidney, and found this caused cyst formation after short latency. Interestingly, the cells lining these cysts frequently lacked a primary cilium, a structure thought to be involved in suppressing cellular proliferation. Although the mechanisms by which these pathways are activated in VHL patients are incompletely understood, this opens the possibility that inhibition of PI3K or ERK signaling pathways may prove effective therapeutic strategies to prevent the loss of primary cilia and inhibit cyst formation and ccRCC formation in VHL patients.
Frew I. J., Thoma C. R., Georgiev S., Minola A., Hitz M., Montani M., Moch H., Krek W. (2008). pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J. May 22 [Epub ahead of print] [doi:
https://doi.org/10.1038/emboj.2008.96].
