Disruption of tubular Flcn expression as a mouse model for renal tumor induction

doi:10.1038/ki.2015.177

. 2015 Nov;88(5):1057-69.

doi: 10.1038/ki.2015.177. Epub 2015 Jun 17.

Disruption of tubular Flcn expression as a mouse model for renal tumor induction

Jindong Chen^{1

2}, Dachuan Huang³, Isabelle Rubera⁴, Kunihiko Futami⁵, Pengfei Wang¹, Peter Zickert⁶, Sok-Kean Khoo⁷, Karl Dykema⁸, Ping Zhao⁹, David Petillo^{8

10}, Brian Cao¹¹, Zhongfa Zhang⁸, Shuhui Si¹, Susan R Schoen¹, Ximing J Yang¹², Ming Zhou¹³, Guang-Qian Xiao¹⁴, Guan Wu¹, Magnus Nordenskjöld¹⁵, Michel Tauc⁴, Bart O Williams¹⁶, Kyle A Furge⁸, Bin Tean Teh^{3

8}

Affiliations

¹ Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
² Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi, China.
³ NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Singapore.
⁴ University of Nice-Sophia Antipolis, Nice, France.
⁵ Course of Applied Marine Biosciences, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, Japan.
⁶ Department of Pathology, Karolinska Institutet, Danderyds Hospital, Stockholm, Sweden.
⁷ Department of Cell and Molecular Biology, Grand Valley State University, Cook-DeVos Center for Health Sciences, Grand Rapids, MI, USA.
⁸ Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
⁹ Spectrum Health, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
¹⁰ Molecular Diagnostics Program, College of Health Professions, Ferris State University, Grand Rapids, MI, USA.
¹¹ Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
¹² Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹³ Department of Pathology, New York University Medical Center, New York, NY, USA.
¹⁴ Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
¹⁵ Clinical Genetics, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI, USA.

PMID: 26083655
DOI: 10.1038/ki.2015.177

Free article

Disruption of tubular Flcn expression as a mouse model for renal tumor induction

Jindong Chen et al. Kidney Int. 2015 Nov.

Free article

. 2015 Nov;88(5):1057-69.

doi: 10.1038/ki.2015.177. Epub 2015 Jun 17.

Authors

Affiliations

¹ Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
² Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi, China.
³ NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Singapore.
⁴ University of Nice-Sophia Antipolis, Nice, France.
⁵ Course of Applied Marine Biosciences, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, Japan.
⁶ Department of Pathology, Karolinska Institutet, Danderyds Hospital, Stockholm, Sweden.
⁷ Department of Cell and Molecular Biology, Grand Valley State University, Cook-DeVos Center for Health Sciences, Grand Rapids, MI, USA.
⁸ Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
⁹ Spectrum Health, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
¹⁰ Molecular Diagnostics Program, College of Health Professions, Ferris State University, Grand Rapids, MI, USA.
¹¹ Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
¹² Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹³ Department of Pathology, New York University Medical Center, New York, NY, USA.
¹⁴ Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
¹⁵ Clinical Genetics, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI, USA.

PMID: 26083655
DOI: 10.1038/ki.2015.177

Abstract

The study of kidney cancer pathogenesis and its treatment has been limited by the scarcity of genetically defined animal models. The FLCN gene that codes for the protein folliculin, mutated in Birt-Hogg-Dubé syndrome, presents a new target for mouse modeling of kidney cancer. Here we developed a kidney-specific knockout model by disrupting the mouse Flcn in the proximal tubules, thus avoiding homozygous embryonic lethality or neonatal mortality, and eliminating the requirement of loss of heterozygosity for tumorigenesis. This knockout develops renal cysts and early onset (6 months) of multiple histological subtypes of renal neoplasms featuring high tumor penetrance. Although the majority of the tumors were chromophobe renal cell carcinomas in affected mice under 1 year of age, papillary renal cell carcinomas predominated in the kidneys of older knockout mice. This renal neoplasia from cystic hyperplasia at 4 months to high-grade renal tumors by 16 months represented the progression of tumorigenesis. The mTOR and TGF-β signalings were upregulated in Flcn-deficient tumors, and these two activated pathways may synergetically cause renal tumorigenesis. Treatment of knockout mice with the mTOR inhibitor rapamycin for 10 months led to the suppression of tumor growth. Thus, our model recapitulates human Birt-Hogg-Dubé kidney tumorigenesis, provides a valuable tool for further study of Flcn-deficient renal tumorigenesis, and tests new drugs/approaches to their treatment.

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References

1. J Cell Biol. 2007 Jul 30;178(3):437-51 - PubMed
1. Histopathology. 2000 Feb;36(2):184-5 - PubMed
1. Cancer Res. 2003 Aug 1;63(15):4583-7 - PubMed
1. EMBO Mol Med. 2013 Jun;5(6):949-64 - PubMed
1. J Urol. 1972 Jul;108(1):58-61 - PubMed

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[1] J Cell Biol. 2007 Jul 30;178(3):437-51 - PubMed

[2] J Cell Biol. 2007 Jul 30;178(3):437-51 - PubMed

[3] Histopathology. 2000 Feb;36(2):184-5 - PubMed

[4] Histopathology. 2000 Feb;36(2):184-5 - PubMed

[5] Cancer Res. 2003 Aug 1;63(15):4583-7 - PubMed

[6] Cancer Res. 2003 Aug 1;63(15):4583-7 - PubMed

[7] EMBO Mol Med. 2013 Jun;5(6):949-64 - PubMed

[8] EMBO Mol Med. 2013 Jun;5(6):949-64 - PubMed

[9] J Urol. 1972 Jul;108(1):58-61 - PubMed

[10] J Urol. 1972 Jul;108(1):58-61 - PubMed

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Disruption of tubular Flcn expression as a mouse model for renal tumor induction

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Disruption of tubular Flcn expression as a mouse model for renal tumor induction

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