Santhakumar, K., Judson, E.C., Elks, P.M., McKee, S., Elworthy, S., van Rooijen, E., Walmsley, S.S., Renshaw, S., Cross, S.S., and van Eeden, F.J. (2012) A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis. Cancer research. 72(16):4017-4027.
Hypoxic signaling is a central modulator of cellular physiology in cancer. Core members of oxygen sensing pathway including
the von Hippel-Lindau tumor suppressor protein (pVHL) and the HIF transcription factors have been intensively studied, but
improved organismal models might speed advances for both pathobiological understanding and therapeutic modulation. To study
HIF signaling during tumorigenesis and development in zebrafish, we developed a unique in vivo reporter for hypoxia, expressing EGFP driven by prolyl hydroxylase 3 (phd3) promoter/regulatory elements. Modulation of HIF pathway in Tg(phd3::EGFP) embryos showed a specific role for hypoxic signaling in the transgene activation. Zebrafish vhl mutants display a systemic hypoxia response, reflected by strong and ubiquitous transgene expression. In contrast to human
VHL patients, heterozygous Vhl mice and vhl zebrafish are not predisposed to cancer. However, upon exposure to dimethylbenzanthracene (DMBA), the vhl heterozygous fish showed an increase in the occurrence of hepatic and intestinal tumors, a subset of which exhibited strong
transgene expression, suggesting loss of Vhl function in these tumor cells. Compared to control fish, DMBA-treated vhl heterozygous fish also showed an increase in proliferating cell nuclear antigen positive renal tubules. Taken together, our
findings establish Vhl as a genuine tumor suppressor in zebrafish and offer this model as a tool to non-invasively study VHL
and HIF signaling during tumorigenesis and development.