Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene

Wenbin Ma, Lino Tessarollo, Seung Beom Hong, Masaya Baba, Eileen Southon, Timothy C. Back, Sally Spence, Corrinne G. Lobe, Nirmala Sharma, Gregory W. Maher, Svetlana Pack, Alexander Vortmeyer, Chuanfa Guo, Berton Zbar, Laura S. Schmidt

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

von Hippel-Lindau (VHL) disease is a multisystem inherited cancer syndrome characterized by the development of highly vascular tumors including hemangioblastomas of the retina and central nervous system, pheochromocytomas, and clear cell renal carcinoma, which result from somatic inactivation of the wild-type VHL allele in cells harboring a germ-line VHL mutation. Homozygous inactivation of the VHL gene in mice resulted in embryonic lethality. To produce a mouse model that closely mimics human VHL disease and avoids embryonic lethality, we used Cre/lox site-specific recombination technology. We generated mice carrying conditional VHL alleles and a cre transgene under the control of the human β-actin promoter, which directs cre expression in a mosaic pattern in multiple organs. VHLf/d/Cre mice developed multiple, hepatic hemangiomas that led to premature death, as well as angiectasis and angiogenesis in multiple organs. Interestingly, testes of male VHLf/d/Cre mice were unusually small with severely reduced sperm count resulting in infertility. Loss of pVHL function in this VHL conditional knockout mouse model results in an extensive abnormal vascular phenotype in multiple mouse organs, which will provide a useful animal model for testing potential antiangiogenic therapies for VHL disease treatment. Importantly, the phenotypic defects in sperm development observed in these mice support a novel role for VHL in spermatogenesis. This VHL conditional knockout mouse model will provide an in vivo system for studying the functional requirement of the VHL gene in reproductive biology.

Original languageEnglish (US)
Pages (from-to)5320-5328
Number of pages9
JournalCancer Research
Volume63
Issue number17
StatePublished - Sep 1 2003
Externally publishedYes

Fingerprint

Spermatogenesis
Blood Vessels
von Hippel-Lindau Disease
Liver
Genes
Neoplasms
Knockout Mice
Alleles
Hemangioblastoma
Premature Mortality
Sperm Count
Pheochromocytoma
Hemangioma
Transgenes
Renal Cell Carcinoma
Germ Cells
Infertility
Genetic Recombination
Retina
Spermatozoa

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ma, W., Tessarollo, L., Hong, S. B., Baba, M., Southon, E., Back, T. C., ... Schmidt, L. S. (2003). Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Research, 63(17), 5320-5328.

Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. / Ma, Wenbin; Tessarollo, Lino; Hong, Seung Beom; Baba, Masaya; Southon, Eileen; Back, Timothy C.; Spence, Sally; Lobe, Corrinne G.; Sharma, Nirmala; Maher, Gregory W.; Pack, Svetlana; Vortmeyer, Alexander; Guo, Chuanfa; Zbar, Berton; Schmidt, Laura S.

In: Cancer Research, Vol. 63, No. 17, 01.09.2003, p. 5320-5328.

Research output: Contribution to journalArticle

Ma, W, Tessarollo, L, Hong, SB, Baba, M, Southon, E, Back, TC, Spence, S, Lobe, CG, Sharma, N, Maher, GW, Pack, S, Vortmeyer, A, Guo, C, Zbar, B & Schmidt, LS 2003, 'Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene', Cancer Research, vol. 63, no. 17, pp. 5320-5328.
Ma, Wenbin ; Tessarollo, Lino ; Hong, Seung Beom ; Baba, Masaya ; Southon, Eileen ; Back, Timothy C. ; Spence, Sally ; Lobe, Corrinne G. ; Sharma, Nirmala ; Maher, Gregory W. ; Pack, Svetlana ; Vortmeyer, Alexander ; Guo, Chuanfa ; Zbar, Berton ; Schmidt, Laura S. / Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. In: Cancer Research. 2003 ; Vol. 63, No. 17. pp. 5320-5328.
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abstract = "von Hippel-Lindau (VHL) disease is a multisystem inherited cancer syndrome characterized by the development of highly vascular tumors including hemangioblastomas of the retina and central nervous system, pheochromocytomas, and clear cell renal carcinoma, which result from somatic inactivation of the wild-type VHL allele in cells harboring a germ-line VHL mutation. Homozygous inactivation of the VHL gene in mice resulted in embryonic lethality. To produce a mouse model that closely mimics human VHL disease and avoids embryonic lethality, we used Cre/lox site-specific recombination technology. We generated mice carrying conditional VHL alleles and a cre transgene under the control of the human β-actin promoter, which directs cre expression in a mosaic pattern in multiple organs. VHLf/d/Cre mice developed multiple, hepatic hemangiomas that led to premature death, as well as angiectasis and angiogenesis in multiple organs. Interestingly, testes of male VHLf/d/Cre mice were unusually small with severely reduced sperm count resulting in infertility. Loss of pVHL function in this VHL conditional knockout mouse model results in an extensive abnormal vascular phenotype in multiple mouse organs, which will provide a useful animal model for testing potential antiangiogenic therapies for VHL disease treatment. Importantly, the phenotypic defects in sperm development observed in these mice support a novel role for VHL in spermatogenesis. This VHL conditional knockout mouse model will provide an in vivo system for studying the functional requirement of the VHL gene in reproductive biology.",
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AU - Southon, Eileen

AU - Back, Timothy C.

AU - Spence, Sally

AU - Lobe, Corrinne G.

AU - Sharma, Nirmala

AU - Maher, Gregory W.

AU - Pack, Svetlana

AU - Vortmeyer, Alexander

AU - Guo, Chuanfa

AU - Zbar, Berton

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