PUBLICATION

A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis

Authors
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.
ID
ZDB-PUB-120607-6
Date
2012
Source
Cancer research   72(16): 4017-4027 (Journal)
Registered Authors
Elks, Phil, Elworthy, Stone, Renshaw, Steve A., Santhakumar, Kiran, van Eeden, Freek, van Rooijen, Ellen
Keywords
none
MeSH Terms
  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Cell Hypoxia/drug effects
  • Cell Hypoxia/physiology
  • Cell Transformation, Neoplastic/chemically induced
  • Cell Transformation, Neoplastic/metabolism*
  • Disease Models, Animal*
  • Hypoxia-Inducible Factor 1/metabolism
  • Intestinal Neoplasms/chemically induced
  • Intestinal Neoplasms/metabolism*
  • Liver Neoplasms, Experimental/chemically induced
  • Liver Neoplasms, Experimental/metabolism*
  • Signal Transduction
  • Tumor Suppressor Proteins/metabolism
  • Zebrafish Proteins/metabolism
PubMed
22665266 Full text @ Cancer Res.
Abstract

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.

Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping