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Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions


Guinot, Anna; Lehmann, Holger; Wild, Peter J; Frew, Ian J (2016). Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions. Journal of Pathology, 239(3):365-373.

Abstract

The von Hippel-Lindau (VHL) tumour suppressor gene is biallelically inactivated in the majority of cases of clear cell renal cell carcinoma (ccRCC), however Vhl knockout mouse models do not recapitulate human ccRCC, implying that additional mutations are required for tumour formation. Mutational inactivation of VHL sensitises renal epithelial cells to lose the primary cilium in response to other mutations or extracellular stimuli. Cilia loss is believed to represent a second hit in VHL mutant cells that causes the development of cystic lesions that in some cases can progress to ccRCC. Supporting this idea, genetic ablation of the primary cilium by deletion of the kinesin family member 3A (Kif3a) gene cooperates with loss of Vhl to accelerate cyst formation in mouse kidneys. Additionally, aged Vhl/Trp53 double mutant mice develop renal cysts and tumours at a relatively low incidence, suggesting that there is a genetic cooperation between VHL and TP53 mutation in the development of ccRCC. Here we generated renal epithelium-specific Kif3a/Trp53 and Vhl/Kif3a/Trp53 mutant mice to investigate whether primary cilium deletion would accelerate the development of cystic precursor lesions or cause their progression to ccRCC. Longitudinal microcomputed tomography imaging and histopathological analyses revealed an increased rate of cyst formation, increased proportion of cysts with proliferating cells, higher frequency of atypical cysts as well as the development of neoplasms in Vhl/Kif3a/Trp53 mutant kidneys compared to Kif3a/Trp53 or Vhl/Kif3a mutant kidneys. These findings demonstrate that primary cilium loss in addition to Vhl and Trp53 losses promotes the transition towards malignancy and provide further evidence that the primary cilium functions as a tumour suppressor organelle in the kidney.

Abstract

The von Hippel-Lindau (VHL) tumour suppressor gene is biallelically inactivated in the majority of cases of clear cell renal cell carcinoma (ccRCC), however Vhl knockout mouse models do not recapitulate human ccRCC, implying that additional mutations are required for tumour formation. Mutational inactivation of VHL sensitises renal epithelial cells to lose the primary cilium in response to other mutations or extracellular stimuli. Cilia loss is believed to represent a second hit in VHL mutant cells that causes the development of cystic lesions that in some cases can progress to ccRCC. Supporting this idea, genetic ablation of the primary cilium by deletion of the kinesin family member 3A (Kif3a) gene cooperates with loss of Vhl to accelerate cyst formation in mouse kidneys. Additionally, aged Vhl/Trp53 double mutant mice develop renal cysts and tumours at a relatively low incidence, suggesting that there is a genetic cooperation between VHL and TP53 mutation in the development of ccRCC. Here we generated renal epithelium-specific Kif3a/Trp53 and Vhl/Kif3a/Trp53 mutant mice to investigate whether primary cilium deletion would accelerate the development of cystic precursor lesions or cause their progression to ccRCC. Longitudinal microcomputed tomography imaging and histopathological analyses revealed an increased rate of cyst formation, increased proportion of cysts with proliferating cells, higher frequency of atypical cysts as well as the development of neoplasms in Vhl/Kif3a/Trp53 mutant kidneys compared to Kif3a/Trp53 or Vhl/Kif3a mutant kidneys. These findings demonstrate that primary cilium loss in addition to Vhl and Trp53 losses promotes the transition towards malignancy and provide further evidence that the primary cilium functions as a tumour suppressor organelle in the kidney.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:29 April 2016
Deposited On:17 May 2016 08:34
Last Modified:02 Sep 2016 06:15
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0022-3417
Publisher DOI:https://doi.org/10.1002/path.4736
PubMed ID:27126173

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