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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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Trisomic expression of Dscr1 is necessary for significant suppression of tumor growth in the Ts65Dn Down syndrome mouse model(a) Possible genotypes arising from mating Ts65Dn and Dscr1+/− mice. (b) Suppression of B16F10 tumor growth in Ts65Dn Down syndrome mice is relieved upon loss of the third copy of Dscr1 (Ts65Dn-Dscr1+/−). Values are mean± sem, n=4–8 per group, *p<0.01. (c) Microvessel density (MVD) per high-powered field (hpf) is quantified by anti-CD31 immunofluorescence of tumors harvested from the indicated mice at comparable volumes (200–400 mm3). Bar, 20 µM. Values are mean ± sem.
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Figure 3: Trisomic expression of Dscr1 is necessary for significant suppression of tumor growth in the Ts65Dn Down syndrome mouse model(a) Possible genotypes arising from mating Ts65Dn and Dscr1+/− mice. (b) Suppression of B16F10 tumor growth in Ts65Dn Down syndrome mice is relieved upon loss of the third copy of Dscr1 (Ts65Dn-Dscr1+/−). Values are mean± sem, n=4–8 per group, *p<0.01. (c) Microvessel density (MVD) per high-powered field (hpf) is quantified by anti-CD31 immunofluorescence of tumors harvested from the indicated mice at comparable volumes (200–400 mm3). Bar, 20 µM. Values are mean ± sem.

Mentions: To confirm that tumor protection in the Ts65Dn mouse was specifically due to Dscr1 trisomy, we crossed the Ts65Dn mice to Dscr1+/− mice18 generating Ts65Dn/Dscr1+/− animals with 2 copies of Dscr1 but maintaining trisomy for the other 103 genes (Fig. 3A). After validating both segmental trisomy and Dscr1 status (Supplemental Fig. 4A and B), we compared flank tumor growth in diploid mice to that in Ts65Dn mice with 2 or 3 copies of Dscr1. Reduction to 2 Dscr1 copies in Ts65Dn/Dscr1+/− mice significantly abrogated the tumor protection observed in Ts65Dn parental mice (Fig. 3B). Loss of the protective effect against tumor growth was mirrored by a corresponding increase in microvessel density in tumors from Ts65Dn/ Dscr1+/− mice relative to their Ts65Dn littermates (Fig. 3C), confirming the pivotal role played by Dscr1 in tumor suppression in the Ts65Dn DS mouse model. Together, our data provide strong support for the notion that 1 extra copy of Dscr1 is necessary for maximal suppression of tumor growth via inhibition of tumor angiogenesis.


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)

Trisomic expression of Dscr1 is necessary for significant suppression of tumor growth in the Ts65Dn Down syndrome mouse model(a) Possible genotypes arising from mating Ts65Dn and Dscr1+/− mice. (b) Suppression of B16F10 tumor growth in Ts65Dn Down syndrome mice is relieved upon loss of the third copy of Dscr1 (Ts65Dn-Dscr1+/−). Values are mean± sem, n=4–8 per group, *p<0.01. (c) Microvessel density (MVD) per high-powered field (hpf) is quantified by anti-CD31 immunofluorescence of tumors harvested from the indicated mice at comparable volumes (200–400 mm3). Bar, 20 µM. Values are mean ± sem.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2724004&req=5

Figure 3: Trisomic expression of Dscr1 is necessary for significant suppression of tumor growth in the Ts65Dn Down syndrome mouse model(a) Possible genotypes arising from mating Ts65Dn and Dscr1+/− mice. (b) Suppression of B16F10 tumor growth in Ts65Dn Down syndrome mice is relieved upon loss of the third copy of Dscr1 (Ts65Dn-Dscr1+/−). Values are mean± sem, n=4–8 per group, *p<0.01. (c) Microvessel density (MVD) per high-powered field (hpf) is quantified by anti-CD31 immunofluorescence of tumors harvested from the indicated mice at comparable volumes (200–400 mm3). Bar, 20 µM. Values are mean ± sem.
Mentions: To confirm that tumor protection in the Ts65Dn mouse was specifically due to Dscr1 trisomy, we crossed the Ts65Dn mice to Dscr1+/− mice18 generating Ts65Dn/Dscr1+/− animals with 2 copies of Dscr1 but maintaining trisomy for the other 103 genes (Fig. 3A). After validating both segmental trisomy and Dscr1 status (Supplemental Fig. 4A and B), we compared flank tumor growth in diploid mice to that in Ts65Dn mice with 2 or 3 copies of Dscr1. Reduction to 2 Dscr1 copies in Ts65Dn/Dscr1+/− mice significantly abrogated the tumor protection observed in Ts65Dn parental mice (Fig. 3B). Loss of the protective effect against tumor growth was mirrored by a corresponding increase in microvessel density in tumors from Ts65Dn/ Dscr1+/− mice relative to their Ts65Dn littermates (Fig. 3C), confirming the pivotal role played by Dscr1 in tumor suppression in the Ts65Dn DS mouse model. Together, our data provide strong support for the notion that 1 extra copy of Dscr1 is necessary for maximal suppression of tumor growth via inhibition of tumor angiogenesis.

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