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

Kirankumar Santhakumar, Emma C Judson, Philip M Elks, Sarah McKee, Stone Elworthy, Ellen van Rooijen, Sarah S Walmsley, Stephen A Renshaw, Simon S Cross, Fredericus J M van Eeden

Research output: Contribution to journalArticlepeer-review

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 hypoxia inducible factor (HIF) transcription factors have been intensively studied, but improved organismal models might speed advances for both pathobiologic 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 with 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 noninvasively study VHL and HIF signaling during tumorigenesis and development.

Original languageEnglish
Pages (from-to)4017-27
Number of pages11
JournalCancer Research
Volume72
Issue number16
DOIs
Publication statusPublished - 15 Aug 2012

Keywords

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Cell Hypoxia
  • Cell Transformation, Neoplastic
  • Disease Models, Animal
  • Hypoxia-Inducible Factor 1
  • Intestinal Neoplasms
  • Liver Neoplasms, Experimental
  • Signal Transduction
  • Tumor Suppressor Proteins
  • Zebrafish Proteins

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