Dr Freek van Eeden PhD
Senior Lecturer in the Department of Biomedical Science
Tel: +44 (0) 114 222 2348
Fax: +44 (0) 114 222 2787
We are exploiting the zebrafish as a powerful vertebrate model to study development and disease. Fish embryos develop rapidly and externally and are transparent, this allows us to follow development of of single cells or tissue at high resolution. We exploit transgenic animals that express flourescent proteins in particular cell types, for instance endothelial cells that for the blood vessels. The genome sequence of zebrafish is highly similar to human, and fish can get similar diseases.
We are interested signaling pathways that can lead to cancer. One model that we are studying is a fish model for "Von Hippel Lindau" disease a dominantly inherited disease where heterozygous human patients develop cysts and tumors in a variety of organs. The protein that is mutated in this disease (Vhl
protein) is normally required to keep and "alarm signal" off that normally would detect low oxygen levels a.k.a. hypoxic signaling. Symptoms in patients are the result of "loss of heterozygosity" in occasional cells that then go on to form cysts of tumours.
Hypoxic signaling leads to stabilisation of a transcription factor named Hypoxia Inducible Factor (HIF). Inappropriate activation of this signal can ultimately lead to cancer. HIF signaling has a major impact on cells and promote adaptations that change the metabolism of the cell towards anaerobic glycolysis and attempts to increase oxygenation by inducing signals that promote blood vessel formation. Since most solid tumors in human grow in size until oxygen "runs out". Therefore HIF induced blood vessel formation plays an important role during growth of a wide variety of tumors.
Fish embryos that lack a functional vhl gene form a lot of extra blood vessel in a way that mimics blood vessel formation in tumours. We are using the fish to understand the factors that govern this process. We are currently looking at how VEGF and Notch interact with other signals to induce angiogenesis. In addition we are trying to understand how the vhl mutation itself promotes tumorigenesis, we have shown that fish vhl mutants are also more susceptible to tumor formation and that these tumors like tumors from human VHL patients have lost their remaining wildtype copy of the gene.
Wilkinson RN, Koudijs MJ, Patient RK, Ingham PW, Schulte-Merker S, van Eeden FJ. Hedgehog signalling via a calcitonin receptor-like receptor can induce arterial differentiation independently of VEGF signalling in zebrafish.
Blood. 2012 Jun 5. [Epub ahead of print]
Santhakumar K, Judson EC, Elks PM, McKee S, Elworthy S, van Rooijen E, Walmsley SS, Renshaw S, Cross SS, van Eeden FJ. A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis. Cancer Res. 2012 Jun 4. [Epub ahead of print]
van Rooijen E, Voest EE, Logister I, Korving J, Schwerte T, Schulte-Merker S, Giles RH, van Eeden FJ. Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Blood. 2009 Jun 18;113(25):6449-60. Epub 2009 Mar 20.