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

Abstract

The incidence of many cancer types is significantly reduced in individuals with Down syndrome1–4 and it is proposed that this broad cancer protection is conferred by the elevated expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is the Down syndrome candidate region-1 (Dscr1, RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling via the calcineurin pathway5–10. Here we show that DSCR1 is elevated in Down syndrome individuals and a mouse model of Down syndrome. Further, we show that the modest elevation in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumor growth in mice and that such resistance is a consequence of a deficit in tumor 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 dramatically diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down syndrome and identifies the calcineurin signalling pathway and its regulators DSCR1 and DYRK1A as potential therapeutic targets in cancers arising in all individuals.

An Indicator for Evaluating the Risk of Cancerous Transformations of Human Induced Pluripotent Stem Cells

“…They suggested that these lesions should be considered to be ''telangiectatic HCA'' (THCA). 4 In 2005, Bioulac-Sage et al reached the same conclusion using different molecular techniques 5 and included in 2007 the so-called ''TFNH'' in the subgroup of inflammatory HCAs. 6 Finally, in 2009, the basis of the inflammatory phenotype was elucidated by the identification of the mutations activating gp130 in most of the inflammatory HCAs exhibiting sinusoidal dilation or not.…”

“…2,3 Furthermore, microvessel density (MVD) has been widely used as a marker of tumor angiogenesis, and has been associated with outcome of cancer therapy. 4 Therefore, we investigated MVD within teratomas in SCID mice into which human iPSCs established by Oct3/4, Sox2, and Klf4, according to the methods of Nakagawa et al, 3 were transplanted.…”

“…4 Next, by using the methods of Shirako et al, 5 we performed knockdown of p21 in the human iPSC lines by p21 small interfering RNA (Fig. 1A, left side).…”

Upregulation of threeDrosophilahomologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome

“…S1 and S2). It is important to note that the levels of intersectin1, synaptojanin1, and DSCR1 proteins have been shown to be elevated at a comparable amount in either human DS patient tissues or Ts65Dn mouse, a commonly used mouse DS model (ranging from Ϸ1.4-to 1.8-fold increases have been reported) (6,(39)(40)(41). Thus, our transgenic flies provide us a model system to investigate whether a dominant key gene or a subset of genes interact to affect phenotypes seen in DS.…”

The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

“…Recently, endostatin and related DS genes have been shown to downregulate VEGF signaling through inhibition of calciumcalcineurin NF-AT (nuclear factor of activated T cells) activities, which attenuate endothelial proliferation and angiogenesis. [137][138][139][140][141][142][143] Whereas these factors may be beneficial for protecting against tumor angiogenesis, we hypothe- . Three-dimensional reconstruction of distal lung tissue, illustrating intrapulmonary arteriovenous communications ("shunt vessels") in infant with severe bronchopulmonary dysplasia (BPD).…”