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Tumour angiogenesis is reduced in the Tc1 mouse model of Down’s syndrome

Nature volume 465, pages 813–817 (2010)Cite this article

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A Corrigendum to this article was published on 15 July 2010

Abstract

Down’s syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours1,2. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes4 (a previously known suppressor of angiogenesis5,6) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS7 to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS18,9and ERG10) and novel endothelial cell-specific genes11, never previously shown to be involved in angiogenesis (JAM-B12 and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.

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Figure 1: Tumour angiogenesis is restricted in Tc1 mice.
Figure 2: VEGF-mediated angiogenic responses are inhibited in Tc1 mice.
Figure 3: Reduction of copy number of candidate genes from three to two can rescue the angiogenic defect in Tc1 mice.
Figure 4: Reduction of copy number from three to one rescues the angiogenic defect in Tc1 mice.

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Acknowledgements

We thank G. Saunders, C. Wren, C. Pegrum and A. Slender for their help with animal husbandry; F. Wiseman and T. Broughton for information on gene deletions in the Tc1 mice; and L. Iruela-Arispe for advice on ADAMTS1 mice and antibody gift.

Author information

Author notes

  1. Alan R. Watson and Marianne Baker: These authors contributed equally to this work.

Authors and Affiliations

  1. Adhesion and Angiogenesis Laboratory, Barts Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK ,

    Louise E. Reynolds, Alan R. Watson, Marianne Baker, Gabriela D’Amico, Stephen D. Robinson & Kairbaan M. Hodivala-Dilke

  2. Centre for Tumour Biology, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK ,

    Carine Joffre, Stephanie Kermorgant & Ian R. Hart

  3. Neuroscience Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Institute of Cell and Molecular Sciences, 4 Newark Street, London E1 2AD, UK ,

    Tania A. Jones & Denise Sheer

  4. Paediatrics Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Institute of Cell and Molecular Sciences, 4 Newark Street, London E1 2AD, UK ,

    Dean Nizetic

  5. Department of Pathology and Immunology, Centre Medical Universitaire, University of Geneva Medical School (CMU), rue Michel Servet 1, CH-1211 Geneva, Switzerland,

    Sarah Garrido-Urbani & Beat A. Imhof

  6. GENYO, Avenida Del Conocimiento, s/n Armilla 18100, Granada, Spain ,

    Juan Carlos Rodriguez-Manzaneque & Estefanía Martino-Echarri

  7. INSERM, 27, Boulevard Lei Roure, 13009 Marseille, France ,

    Michel Aurrand-Lions

  8. Human Genetics Institute, Galliere Hospital, Via Volta 10, 16128 Genoa, Italy ,

    Franca Dagna-Bricarelli

  9. School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK

    Christopher J. McCabe

  10. School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK

    Andrew S. Turnell

  11. Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, D-48149 Münster, Germany ,

    Ralf Adams

  12. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK,

    Elizabeth M. C. Fisher

  13. Division of Immune Cell Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK,

    Victor L. J. Tybulewicz

Authors
  1. Louise E. Reynolds
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Contributions

L.E.R. and K.M.H-D. designed the experiments. L.E.R. performed the experiments. A.R.W. performed the bone marrow transplant experiments and stained for Y chromosome and conducted RT–PCR. G.D’A. performed the aortic ring assay. S.D.R. performed the phospho-VEGFR2 western blot analysis. T.A.J. and D.S. performed the tumour cell karyotyping. M.B. assisted with the immunostaining, tumour and sponge harvesting and flow cytometric analysis. C.J. and S.K. conducted flow cytometry and immunofluorescence of cells. B.A.I., R.A. and S.G.-U. supplied the JAM-B antibodies for western blot analysis and JAM-B wild-type and heterozygous mice for in vivo and ex vivo studies and JAM-B biochemistry in JAM-B heterozygotes. J.C.R.-M. and E.M.-E. provided the ADAMTS1 heterozygous aortae and ADAMTS1 PCR analysis. C.J.M. and A.T. provided the PTTG1IP antibody for western blot analysis. F.D.-B. and D.N. provided the human DS and normal control cells. V.J.T. and E.M.C.F. designed , developed and provided the Tc1 mice. L.E.R., K.M.H-D. and I.R.H. wrote the paper with substantial input from the other authors.

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Correspondence to Louise E. Reynolds.

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Reynolds, L., Watson, A., Baker, M. et al. Tumour angiogenesis is reduced in the Tc1 mouse model of Down’s syndrome. Nature 465, 813–817 (2010). https://doi.org/10.1038/nature09106

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