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

Nature. 2010 Jun 10;465(7299):813-7. doi: 10.1038/nature09106.

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 tumours. 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) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS 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 (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B 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.

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAMTS1 Protein
  • Animals
  • Carcinoma, Lewis Lung / blood supply*
  • Carcinoma, Lewis Lung / complications
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Chromosomes, Mammalian / genetics
  • Disease Models, Animal*
  • Down Syndrome / complications
  • Down Syndrome / genetics*
  • Down Syndrome / physiopathology
  • Female
  • Gene Dosage / genetics*
  • Humans
  • Immunoglobulins / genetics
  • Immunoglobulins / metabolism
  • Male
  • Melanoma, Experimental / blood supply*
  • Melanoma, Experimental / complications
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology
  • Mice
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / pathology
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Proto-Oncogene Protein c-ets-2 / genetics
  • Proto-Oncogene Protein c-ets-2 / metabolism
  • Transcription Factors
  • Transcriptional Regulator ERG
  • Trisomy / genetics
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Carrier Proteins
  • Cell Adhesion Molecules
  • ERG protein, mouse
  • Ets2 protein, mouse
  • Immunoglobulins
  • Jam2 protein, mouse
  • Oncogene Proteins
  • PTTG1IP protein, mouse
  • Proto-Oncogene Protein c-ets-2
  • Transcription Factors
  • Transcriptional Regulator ERG
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2
  • ADAM Proteins
  • ADAMTS1 Protein
  • Adamts1 protein, mouse