title: Disruption of tubular Flcn expression as a mouse model for renal tumor induction.
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.
authors.affiliation: Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.|Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi, China.
authors.forename: Jindong
authors.initials: J
authors.lastname: Chen
authors.affiliation: NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Singapore.
authors.forename: Dachuan
authors.initials: D
authors.lastname: Huang
authors.affiliation: University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rubera
authors.affiliation: Course of Applied Marine Biosciences, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Futami
authors.affiliation: Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pathology, Karolinska Institutet, Danderyds Hospital, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Zickert
authors.affiliation: Department of Cell and Molecular Biology, Grand Valley State University, Cook-DeVos Center for Health Sciences, Grand Rapids, MI, USA.
authors.forename: Sok-Kean
authors.initials: SK
authors.lastname: Khoo
authors.affiliation: Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Dykema
authors.affiliation: Spectrum Health, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.|Molecular Diagnostics Program, College of Health Professions, Ferris State University, Grand Rapids, MI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Cao
authors.affiliation: Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Si
authors.affiliation: Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Schoen
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Ximing J
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: Department of Pathology, New York University Medical Center, New York, NY, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Guang-Qian
authors.initials: GQ
authors.lastname: Xiao
authors.affiliation: Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Guan
authors.initials: G
authors.lastname: Wu
authors.affiliation: Clinical Genetics, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.affiliation: University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.affiliation: Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.affiliation: Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Furge
authors.affiliation: NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Singapore.|Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D063646:Carcinogenesis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D003560:Cysts / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D006965:Hyperplasia / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; C526060:Bhd protein, mouse; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus