Endogenous Angiogenesis Inhibition

Science Signaling  30 Jun 2009:
Vol. 2, Issue 77, pp. ec215
DOI: 10.1126/scisignal.277ec215

Down syndrome, which is caused by the presence of an extra copy of chromosome 21 and is the most common genetic cause of mental retardation, is associated with a substantially decreased risk of most solid cancers. DSCR1, one of the supernumerary genes in trisomy 21, encodes a protein that inhibits angiogenic signaling mediated through vascular endothelial growth factor (VEGF) and calcineurin. This inhibition led Baek et al. to explore the possibility that increased DSCR1 abundance might suppress angiogenesis and, thereby, tumor growth. After determining that there was indeed a modest increase in DSCR1 abundance in Down syndrome tissues, the authors identified a comparable increase in DSCR1 in the Ts65Dn mouse model of Down syndrome, which is trisomic for the mouse orthologs of 104 of the human chromosome 21 genes. Transplanted tumors grew more slowly in Ts65Dn mice than in diploid littermates and showed decreased microvessel density; moreover, teratomas derived from induced pluripotent stem cells with trisomy 21 had lower microvessel density when grown in immunodeficient mice than did teratomas derived from cytogenically normal cells. Transgenic mice with three copies of Dscr1 (Dscr1 mice) also showed decreased growth of transplanted tumors and decreased tumor angiogenesis, whereas Ts65Dn mice with only two copies of Dscr1 (but trisomic for the other 103 genes) exhibited tumor growth and angiogenesis intermediate between those of parent Ts65Dn and wild-type mice. Compared with wild-type cells, endothelial cells from Dscr1 mice showed decreased VEGF-calcineurin signaling, as evidenced by decreased translocation of NFATc1 to the nucleus in response to VEGF treatment, decreased abundance of the VEGF-calcineurin-NFAT target cycloxygenase 2, and decreased VEGF-induced proliferation. Overexpression in Dscr1 transgenic endothelial cells of another chromosome 21 gene implicated in VEGF signaling, Dyrk1a, further decreased VEGF-dependent endothelial cell proliferation. The authors conclude that inhibition of angiogenesis by DSCR1 through the VEGF-calcineurin pathway likely contributes to the decreased incidence of tumors in individuals with Down syndrome and may provide clues to new therapeutic targets in cancer.

K.-H. Baek, A. Zaslavsky, R. C. Lynch, C. Britt, Y. Okada, R. J. Siarey, M. W. Lensch, I.-H. Park, S. S. Yoon, T. Minami, J. R. Korenberg, J. Folkman, G. Q. Daley, W. C. Aird, Z. Galdzicki, S. Ryeom, Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459, 1126–1130 (2009). [PubMed]