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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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.
The authors declare no competing financial interests.
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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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