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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model

Authors: Hannah L. Bader, Tien Hsu

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome—VHL disease—and are also frequently observed in sporadic renal cell carcinoma of the clear cell type (ccRCC). VHL disease is characterized by malignant and benign tumors in a few specific tissues, including ccRCC, hemangioblastoma and pheochromocytoma. The etiology of these tumors remains unresolved.

Methods

Conditional inactivation of the VHL gene in mouse (Vhlh) was generated to examine the pathophysiological role of the VHL gene function. Specific cell populations were isolated by fluorescence-activated cell sorting (FACS) and bone marrow transplants were performed to identify the Vhlh-inactivated cells responsible for the phenotype.

Results

Previously we showed that inactivation of Vhlh in a subpopulation of kidney distal tubule cells resulted in hyperplastic clear-cell lesions and severe inflammation and fibrosis. Here, we show that this knockout mouse strain also develops Hif-2α-dependent vascular overgrowth (hemangioma) and extramedullary erythropoiesis in the liver. However, Vhlh inactivation was not detected in the liver parenchyma. We instead demonstrate that in these mice, Vhlh is inactivated in liver granulocytes and that hemangiomas are partially rescued in knockout mice reconstituted with wild-type hematopoietic stem cells, indicating the involvement of bone-marrow-derived leukocyte. Interestingly, bone marrow from knockout mice failed to generate the liver phenotype in wild-type recipients, suggesting that an additional cell type that is not derived from the bone marrow is involved in the development of the hemangioma phenotype.

Conclusion

These results support the idea that the development of a full-blown VHL disease phenotype requires inactivation of the VHL gene not only in the tumor proper, but also in the stromal compartment.
Literature
1.
Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2014;15(1):55–64.CrossRef
2.
Ang SO, Chen H, Gordeuk VR, Sergueeva AI, Polyakova LA, Miasnikova GY, Kralovics R, Stockton DW, Prchal JT. Endemic polycythemia in Russia: mutation in the VHL gene. Blood Cells Mol Dis. 2002;28(1):57–62.CrossRefPubMed
3.
Pastore YD, Jelinek J, Ang S, Guan Y, Liu E, Jedlickova K, Krishnamurti L, Prchal JT. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood. 2003;101(4):1591–5.CrossRefPubMed
4.
Tomasic NL, Piterkova L, Huff C, Bilic E, Yoon D, Miasnikova GY, Sergueeva AI, Niu X, Nekhai S, Gordeuk V, et al. The phenotype of polycythemia due to Croatian homozygous VHL (571C > G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C > T:R200W). Haematologica. 2013;98(4):560–7.CrossRefPubMedPubMedCentral
5.
Shen C, Kaelin Jr WG. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013;23(1):18–25.CrossRefPubMed
6.
Hsu T. Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: insights from model organisms. Oncogene. 2012;31(18):2247–57.CrossRefPubMed
7.
Jonasch E, Futreal PA, Davis IJ, Bailey ST, Kim WY, Brugarolas J, Giaccia AJ, Kurban G, Pause A, Frydman J, et al. State of the science: an update on renal cell carcinoma. Mol Cancer Res. 2012;10(7):859–80.CrossRefPubMedPubMedCentral
8.
Cancer Genome Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–9.CrossRef
9.
Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, Shimamura T, Sato-Otsubo A, Nagae G, Suzuki H, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45(8):860–7.CrossRefPubMed
10.
11.
Wang SS, Gu YF, Wolff N, Stefanius K, Christie A, Dey A, Hammer RE, Xie XJ, Rakheja D, Pedrosa I, et al. Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proc Natl Acad Sci U S A. 2014;111(46):16538–43.CrossRefPubMedPubMedCentral
12.
Eng C, Leone G, Orloff MS, Ostrowski MC. Genomic alterations in tumor stroma. Cancer Res. 2009;69(17):6759–64.CrossRefPubMed
13.
14.
Lee JY, Dong SM, Park WS, Yoo NJ, Kim CS, Jang JJ, Chi JG, Zbar B, Lubensky IA, Linehan WM, et al. Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res. 1998;58(3):504–8.PubMed
15.
Vortmeyer AO, Gnarra JR, Emmert-Buck MR, Katz D, Linehan WM, Oldfield EH, Zhuang Z. von Hippel-Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel-Lindau disease. Hum Pathol. 1997;28(5):540–3.CrossRefPubMed
16.
Vortmeyer AO, Huang SC, Pack SD, Koch CA, Lubensky IA, Oldfield EH, Zhuang Z. Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion. Oncogene. 2002;21(8):1167–70.CrossRefPubMed
17.
Park DM, Zhuang Z, Chen L, Szerlip N, Maric I, Li J, Sohn T, Kim SH, Lubensky IA, Vortmeyer AO, et al. von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med. 2007;4(2):e60.CrossRefPubMedPubMedCentral
18.
Vortmeyer AO, Frank S, Jeong SY, Yuan K, Ikejiri B, Lee YS, Bhowmick D, Lonser RR, Smith R, Rodgers G, et al. Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res. 2003;63(21):7051–5.PubMed
19.
Vortmeyer AO, Tran MG, Zeng W, Glasker S, Riley C, Tsokos M, Ikejiri B, Merrill MJ, Raffeld M, Zhuang Z, et al. Evolution of VHL tumourigenesis in nerve root tissue. J Pathol. 2006;210(3):374–82.CrossRefPubMed
20.
Haase VH, Glickman JN, Socolovsky M, Jaenisch R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A. 2001;98(4):1583–8.CrossRefPubMedPubMedCentral
21.
Ma W, Tessarollo L, Hong SB, Baba M, Southon E, Back TC, Spence S, Lobe CG, Sharma N, Maher GW, et al. Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Res. 2003;63(17):5320–8.PubMed
22.
Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA, Haase VH. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol. 2005;25(8):3163–72.CrossRefPubMedPubMedCentral
23.
Kleymenova E, Everitt JI, Pluta L, Portis M, Gnarra JR, Walker CL. Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice. Carcinogenesis. 2004;25(3):309–15.CrossRefPubMed
24.
Rankin EB, Rha J, Unger TL, Wu CH, Shutt HP, Johnson RS, Simon MC, Keith B, Haase VH. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene. 2008;27(40):5354–8.CrossRefPubMedPubMedCentral
25.
Pritchett TL, Bader HL, Henderson J, Hsu T. Conditional inactivation of the mouse von Hippel-Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney. Oncogene. 2015;34(20):2631–9.CrossRefPubMed
26.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996;183(4):1797–806.CrossRefPubMed
27.
Mostoslavsky G, Kotton DN, Fabian AJ, Gray JT, Lee JS, Mulligan RC. Efficiency of transduction of highly purified murine hematopoietic stem cells by lentiviral and oncoretroviral vectors under conditions of minimal in vitro manipulation. Mol Ther. 2005;11(6):932–40.CrossRefPubMed
28.
Yu J, Carroll TJ, McMahon AP. Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development. 2002;129(22):5301–12.PubMed
29.
Zhao H, Kegg H, Grady S, Truong HT, Robinson ML, Baum M, Bates CM. Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev Biol. 2004;276(2):403–15.CrossRefPubMedPubMedCentral
30.
Li J, Hale J, Bhagia P, Xue F, Chen L, Jaffray J, Yan H, Lane J, Gallagher PG, Mohandas N, et al. Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E. Blood. 2014;124(24):3636–45.CrossRefPubMedPubMedCentral
31.
Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999;21(1):70–1.CrossRefPubMed
32.
Sasmono RT, Ehrnsperger A, Cronau SL, Ravasi T, Kandane R, Hickey MJ, Cook AD, Himes SR, Hamilton JA, Hume DA. Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1. J Leukoc Biol. 2007;82(1):111–23.CrossRefPubMed
33.
Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M, Montani M, Moch H, Krek W. pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. Embo J. 2008;27(12):1747–57.CrossRefPubMedPubMedCentral
34.
Glasker S, Kruger MT, Klingler JH, Wlodarski M, Klompen J, Schatlo B, Hippchen B, Neumann HP, Van Velthoven V. Hemangioblastomas and neurogenic polyglobulia. Neurosurgery. 2013;72(6):930–5.CrossRefPubMed
35.
36.
Christoffersson G, Vagesjo E, Vandooren J, Liden M, Massena S, Reinert RB, Brissova M, Powers AC, Opdenakker G, Phillipson M. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood. 2012;120(23):4653–62.CrossRefPubMedPubMedCentral
Metadata
Title
Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model
Authors
Hannah L. Bader
Tien Hsu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2802-3

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