Publication Date:
2010-06-11
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479956/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479956/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reynolds, Louise E -- Watson, Alan R -- Baker, Marianne -- Jones, Tania A -- D'Amico, Gabriela -- Robinson, Stephen D -- Joffre, Carine -- Garrido-Urbani, Sarah -- Rodriguez-Manzaneque, Juan Carlos -- Martino-Echarri, Estefania -- Aurrand-Lions, Michel -- Sheer, Denise -- Dagna-Bricarelli, Franca -- Nizetic, Dean -- McCabe, Christopher J -- Turnell, Andrew S -- Kermorgant, Stephanie -- Imhof, Beat A -- Adams, Ralf -- Fisher, Elizabeth M C -- Tybulewicz, Victor L J -- Hart, Ian R -- Hodivala-Dilke, Kairbaan M -- 080174/Wellcome Trust/United Kingdom -- 12007/Cancer Research UK/United Kingdom -- A12007/Cancer Research UK/United Kingdom -- A3585/Cancer Research UK/United Kingdom -- G0501003/Medical Research Council/United Kingdom -- G0501003(75694)/Medical Research Council/United Kingdom -- G0601056/Medical Research Council/United Kingdom -- G0901609/Medical Research Council/United Kingdom -- MC_U117527252/Medical Research Council/United Kingdom -- U.1175.02.001.00001(60485)/Medical Research Council/United Kingdom -- England -- Nature. 2010 Jun 10;465(7299):813-7. doi: 10.1038/nature09106.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. l.reynolds@qmul.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535211" target="_blank"〉PubMed〈/a〉
Keywords:
ADAM Proteins/genetics/metabolism
;
Animals
;
Carcinoma, Lewis Lung/*blood supply/complications/genetics/pathology
;
Carrier Proteins/genetics/metabolism
;
Cell Adhesion Molecules/antagonists & inhibitors/genetics/metabolism
;
Chromosomes, Mammalian/genetics
;
*Disease Models, Animal
;
Down Syndrome/complications/*genetics/physiopathology
;
Female
;
Gene Dosage/*genetics
;
Humans
;
Immunoglobulins/genetics/metabolism
;
Male
;
Melanoma, Experimental/*blood supply/complications/genetics/pathology
;
Mice
;
Neoplasm Transplantation
;
Neovascularization, Pathologic/*genetics/pathology
;
Oncogene Proteins/genetics/metabolism
;
Proto-Oncogene Protein c-ets-2/genetics/metabolism
;
Transcription Factors
;
Trisomy/genetics
;
Vascular Endothelial Growth Factor A/antagonists &
;
inhibitors/metabolism/pharmacology
;
Vascular Endothelial Growth Factor Receptor-2/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
