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Models of Von
Hippel-Lindau tumor suppressor disease specific activity
W. K. Rathmell, C. Chmielecki, T. Van Dyke, M. C. Simon
University of North Carolina, Chapel Hill, NC; University of
Pennsylvania, Philadelphia, PA
Background.
The Von Hippel-Lindau (VHL) syndrome is an autosomal dominant
disorder characterized by mutations in a classical tumor suppressor gene (VHL).
Clear cell renal cell carcinoma and hemangioblastoma without pheochromocytoma
characterize VHL type 1 disease.
VHL type 2 disease is characterized by the presence of pheochromocytoma and is
further subdivided into type 2A (pheochromocytoma and hemangioblastoma), 2B
(pheochromocytoma, renal cell carcinoma, and hemangioblastoma), and 2C
(pheochromocytoma only).
VHL has been implicated in cellular processes important for
tumorigenesis, including cell cycle control, extra-cellular matrix remodeling,
response to oxygen deprivation, and angiogenesis.
The importance of VHL in each of these processes as they pertain to
tumorigenesis is unknown.
Methods.
To address the hypothesis that pVHL performs multiple functions
within the cell, and perturbation of individual functions via missense mutations
contributes to the tissue specificity of the VHL syndrome tumors, we have
generated a panel of VHL mutations representative of the VHL disease
subtypes in both tissue culture and transgenic animal model systems by both
transgenic and gene targeting approaches.
Results.
Embryonic stem cells which express only mutant forms of the VHL
protein were examined in vitro for activation of the hypoxic response pathway,
and demonstrate a restricted pattern of HIF1a and HIF2a activation, which
correlates with predisposition to clear cell renal cell carcinoma.
Furthermore, in teratomas derived from these ES cells on nude mice, we observed
defects of tumor development, angiogenesis, as well as fibronectin deposition,
which also correlate to the mutation of VHL expressed.
Conclusions.
This strategy utilizes three models systems: tissue culture,
xenograft, and in vivo animal models to create distinctions between uniquely
tissue specific types of tumorigenesis.
Our findings of regulated HIF expression and HIF target gene expression as well
as effects on vasculogenesis mimic those observed in human disease and provides
a molecular mechanism to account for the highly vascular phenotype of VHL
associated tumors.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-00431,00.asp
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