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[Cancer Research 63, 5320-5328, September 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Hepatic Vascular Tumors, Angiectasis in Multiple Organs, and Impaired Spermatogenesis in Mice with Conditional Inactivation of the VHL Gene1

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 O. Vortmeyer, Chuanfa Guo, Berton Zbar and Laura S. Schmidt2

Laboratory of Immunobiology, Center for Cancer Research [W. M., S-B. H., N. S., G. W. M., B. Z.], Mouse Cancer Genetics Program [L. T., S. S.], Laboratory of Animal Sciences [E. S.], and Basic Research Program [T. C. B., L. S. S.], Science Applications International Corporation-Frederick, Inc., National Cancer Institute Frederick, Frederick, Maryland 21702; Department of Urology, Yokohama City School of Medicine, Yokohama, 236 Japan [M. B.]; Molecular and Cellular Biology Research, Sunnybrook and Women’s College Health Centre, Toronto, Ontario, Canada M4N 3M5 [C. G. L.]; Surgical Neurology Branch, National Institute of Neurologic Disease, Blindness and Stroke, Bethesda, Maryland 20894 [S. P., A. O. V.]; and Department of Epidemiology and Preventive Medicine, University of Maryland at Baltimore, Baltimore, Maryland 21210 [C. G.]

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 ß-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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