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Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.

Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S - Nature (2009)

Bottom Line: The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21.We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis.These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA.

ABSTRACT
The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

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Dscr1 expression is upregulated in Down syndrome tissues and tumor angiogenesis is suppressed in Down syndrome models(a) Increased DSCR1 expression in human fetal Down syndrome (DS) tissues versus age-matched control (ctrl) tissues relative to β-actin. (b) Tumor growth is suppressed in the Ts65Dn Down syndrome mouse model. Values are mean ± s.e.m. n=10–12, *p<0.03; **p <0.01. (c) Microvessel density (MVD) per high-powered field (hpf) of tumors is quantified by anti-CD31 immunofluorescence. Bar, 20 µM. Values are mean ± s.e.m. *p <0.02; **p<0.01. (d) Angiogenesis in tumors from induced pluripotent stem cells (iPS) isolated from Down syndrome or cytogenetically normal cells was quantified by human specific anti-CD31 immunofluorescence. Arrows, hCD31-positive vessels. Values are mean ± s.e.m. n=3–6, **p<0.01.
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Figure 1: Dscr1 expression is upregulated in Down syndrome tissues and tumor angiogenesis is suppressed in Down syndrome models(a) Increased DSCR1 expression in human fetal Down syndrome (DS) tissues versus age-matched control (ctrl) tissues relative to β-actin. (b) Tumor growth is suppressed in the Ts65Dn Down syndrome mouse model. Values are mean ± s.e.m. n=10–12, *p<0.03; **p <0.01. (c) Microvessel density (MVD) per high-powered field (hpf) of tumors is quantified by anti-CD31 immunofluorescence. Bar, 20 µM. Values are mean ± s.e.m. *p <0.02; **p<0.01. (d) Angiogenesis in tumors from induced pluripotent stem cells (iPS) isolated from Down syndrome or cytogenetically normal cells was quantified by human specific anti-CD31 immunofluorescence. Arrows, hCD31-positive vessels. Values are mean ± s.e.m. n=3–6, **p<0.01.

Mentions: The Dscr1 gene lies on chromosome 21 and encodes a negative regulator of VEGF-calcineurin signalling in the endothelium5–10. Previous studies have demonstrated that gross over-expression of DSCR1 in endothelial cells blocks VEGF-mediated angiogenic responses in vitro7–10. We examined DSCR1 protein expression in DS human fetal tissues and observed a consistent 1.8-fold increase in DSCR1 levels in tissues from DS embryos, as well as elevated expression of DSCR1 fetal isoforms5, compared with those from age-matched non-DS fetuses (Fig. 1A). Substantial synteny exists in gene identity and order between much of human chromosome 21 and the mouse13. The Ts65Dn mouse model of DS is trisomic for 104 of the 231 genes on human chromosome 21 including DSCR114 (Supplemental Fig. 1A). We probed tissues from Ts65Dn mice to ascertain whether DSCR1 was also upregulated in the Ts65Dn mouse and found a 1.7-fold increase in DSCR1 protein expression compared with diploid littermates (Supplemental Fig. 1B). Thus, DSCR1 expression in Ts65Dn mice is elevated in an analogous fashion to DSCR1 expression in DS fetal tissues.


Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.

Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S - Nature (2009)

Dscr1 expression is upregulated in Down syndrome tissues and tumor angiogenesis is suppressed in Down syndrome models(a) Increased DSCR1 expression in human fetal Down syndrome (DS) tissues versus age-matched control (ctrl) tissues relative to β-actin. (b) Tumor growth is suppressed in the Ts65Dn Down syndrome mouse model. Values are mean ± s.e.m. n=10–12, *p<0.03; **p <0.01. (c) Microvessel density (MVD) per high-powered field (hpf) of tumors is quantified by anti-CD31 immunofluorescence. Bar, 20 µM. Values are mean ± s.e.m. *p <0.02; **p<0.01. (d) Angiogenesis in tumors from induced pluripotent stem cells (iPS) isolated from Down syndrome or cytogenetically normal cells was quantified by human specific anti-CD31 immunofluorescence. Arrows, hCD31-positive vessels. Values are mean ± s.e.m. n=3–6, **p<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2724004&req=5

Figure 1: Dscr1 expression is upregulated in Down syndrome tissues and tumor angiogenesis is suppressed in Down syndrome models(a) Increased DSCR1 expression in human fetal Down syndrome (DS) tissues versus age-matched control (ctrl) tissues relative to β-actin. (b) Tumor growth is suppressed in the Ts65Dn Down syndrome mouse model. Values are mean ± s.e.m. n=10–12, *p<0.03; **p <0.01. (c) Microvessel density (MVD) per high-powered field (hpf) of tumors is quantified by anti-CD31 immunofluorescence. Bar, 20 µM. Values are mean ± s.e.m. *p <0.02; **p<0.01. (d) Angiogenesis in tumors from induced pluripotent stem cells (iPS) isolated from Down syndrome or cytogenetically normal cells was quantified by human specific anti-CD31 immunofluorescence. Arrows, hCD31-positive vessels. Values are mean ± s.e.m. n=3–6, **p<0.01.
Mentions: The Dscr1 gene lies on chromosome 21 and encodes a negative regulator of VEGF-calcineurin signalling in the endothelium5–10. Previous studies have demonstrated that gross over-expression of DSCR1 in endothelial cells blocks VEGF-mediated angiogenic responses in vitro7–10. We examined DSCR1 protein expression in DS human fetal tissues and observed a consistent 1.8-fold increase in DSCR1 levels in tissues from DS embryos, as well as elevated expression of DSCR1 fetal isoforms5, compared with those from age-matched non-DS fetuses (Fig. 1A). Substantial synteny exists in gene identity and order between much of human chromosome 21 and the mouse13. The Ts65Dn mouse model of DS is trisomic for 104 of the 231 genes on human chromosome 21 including DSCR114 (Supplemental Fig. 1A). We probed tissues from Ts65Dn mice to ascertain whether DSCR1 was also upregulated in the Ts65Dn mouse and found a 1.7-fold increase in DSCR1 protein expression compared with diploid littermates (Supplemental Fig. 1B). Thus, DSCR1 expression in Ts65Dn mice is elevated in an analogous fashion to DSCR1 expression in DS fetal tissues.

Bottom Line: The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21.We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis.These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA.

ABSTRACT
The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

Show MeSH
Related in: MedlinePlus