Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome.
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.
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
Louise E
LE
Reynolds
Alan R
AR
Watson
Marianne
M
Baker
Tania A
TA
Jones
Gabriela
G
D'Amico
Stephen D
SD
Robinson
Carine
C
Joffre
Sarah
S
Garrido-Urbani
Juan Carlos
JC
Rodriguez-Manzaneque
Estefanía
E
Martino-Echarri
Michel
M
Aurrand-Lions
Denise
D
Sheer
Franca
F
Dagna-Bricarelli
Dean
D
Nizetic
Christopher J
CJ
McCabe
Andrew S
AS
Turnell
Stephanie
S
Kermorgant
Beat A
BA
Imhof
Ralf
R
Adams
Elizabeth M C
EM
Fisher
Victor L J
VL
Tybulewicz
Ian R
IR
Hart
Kairbaan M
KM
Hodivala-Dilke
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071097:ADAMTS1 Protein; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000150:complications / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000150:complications / Q000235:genetics / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D014314:Trisomy / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D062765:Junctional Adhesion Molecule B
D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D050787:Proto-Oncogene Protein c-ets-2; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C531115:ERG protein, mouse; C494070:Ets2 protein, mouse; C498781:Jam2 protein, mouse; D062765:Junctional Adhesion Molecule B; C550910:PTTG1IP protein, mouse; C486323:Adamts1 protein, mouse