Posted by: barn owl | February 2, 2008

Down Syndrome Mouse Models: Trisomy Represses Formation of Intestinal Tumors
Down Syndrome (DS), or trisomy 21, is the most frequent genetic cause of mental retardation, and occurs with an incidence of 1:700 live births. In addition to the characteristic facial appearance, altered brain structure, poor muscle tone, and early onset Alzheimer’s pathology associated with trisomy 21, individuals with DS are at increased risk of mortality due to congenital heart abnormalities, respiratory infections, and leukemia. In contrast, malignant solid tumors are underrepresented in the cohort of DS patients, perhaps by as much as a factor of ten (Yang et al., 2002). To begin to identify potential tumor suppressor genes on chromosome 21, or to identify other mechanisms that might account for the reduced incidence of malignant solid tumors in individuals with DS, Sussan et al. (2008) used aneuploid mouse models for Down Syndrome, combined with a mouse model for an inherited intestinal tumor syndrome (familial adenomatous polyposis).

The Apc(min/+) mouse harbors a point mutation in the adenomatous polyposis coli gene, which is embryonic lethal in the homozygous state. The heterozygotes, however, spontaneously develop multiple intestinal tumors with complete penetrance, beginning at a few weeks of age. This animal model for colorectal carcinogenesis has been used to identify modifying genes that either suppress or accelerate the formation of intestinal tumors (Yamada and Mori, 2007). Just such a well-characterized and robust tumorigenesis model was required to test the “anti-cancer” properties of trisomy 21.

Orthologues of genes on Hsa21 exist in the same order on mouse chromosome 16 (Mmu16), an arrangement that has been exploited to generate mouse models of Down Syndrome. The most widely used model, Ts65Dn, has partial (segmental) trisomy for about half of the Hsa21 orthologues, and exhibits many of the characteristics of human DS, including small size and craniofacial abnormalities. The Ts1Rhr mouse represents segmental trisomy for only 33 genes in the “Down Syndrome critical region”, yet does not exhibit the dysmorphic craniofacial features or the body size reduction (Olson et al., 2004). In the Sussan et al. (2008) paper, however, both the Ts65Dn and the Ts1Rhr segmental trisomies significantly reduced intestinal tumor number (44% and 26% reduction, respectively), when combined with the Apc(min/+) tumor-prone genetic background. Conversely, segmental monosomy for the 33 genes (Ms1Rhr) resulted in a 101% increase in intestinal tumor number.

Candidate genes in the dosage imbalance Mmu16 segment included the Ets “pro-cancer” gene, which also possesses “anti-cancer” functions at early stages of transformation. By introducing inactivating targeted mutations in the Ets gene, while leaving the flanking 32 genes in Ts1Rhr intact, Sussan et al. (2008) demonstrated that much of the tumor repression, at least with respect to tumor number, in their segmental trisomy construct can be attributed to the extra copy of the Ets gene. However, careful analysis of individual tumor size revealed a reduction for Ts65Dn mice, but not for the Ts1Rhr mice, indicating that (as yet unidentified) genes in addition to Ets are involved in the tumor-inhibiting activity of the segmental trisomy. The authors emphasize two important aspects of their work: 1) variation in the expression levels of oncogenes or tumor suppressor genes can affect tumorigenesis in different ways, 2) if trisomy 21 were lethal (as are most trisomies in humans), a possible genetic means of promoting tumor resistance (through manipulation of Ets) would not have been identified.

Additional References:

Olson, L.E., Richtsmeier, J.T., Leszl, J., and Reeves, R.H. (2004). A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306, 687-690.

Yamada, Y., Mori, H. (2007). Multistep carcinogenesis of the colon in Apc(min/+) mouse. Cancer Sci. 98, 6-10.

Yang, Q., Rasmussen, S.A., Friedman, J.M. (2002). Mortality associated with Down’s syndrome in the USA from 1982 to 1997: a population-based study. Lancet 359, 1019-1025.

*First in a series of Weekend Disease Models posts, blogging on peer-reviewed research*

Sussan, T.E., Yang, A., Li, F., Ostrowski, M.C., Reeves, R.H. (2008). Trisomy represses ApcMin-mediated tumours in mouse models of Down’s syndrome. Nature, 451(7174), 73-75. DOI: 10.1038/nature06446

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  1. Thanks for this — I’ve been meaning to do a review of the nature paper since it was published, but have been without access to a subscription. I wrote about the tumour suppressive effect of Down’s last year. The story as I understood it at the time was that, because leukaemias are less common, the simplest explanation was that something specific to solid tumours was the problem, and a lot of the literature was therefore focused on angiogenesis.

  2. Genes that affect angiogenesis could still be players in the trisomy 21 tumor-suppressive effects, since the TsRhr1 construct reduced tumor number, but not individual tumor size. I was reminded of the classic Vogelstein tumor progression scenario, with mutations in multiple genes required for invasiveness, escape from apoptosis or cell cycle arrest, and metastasis.

    I enjoyed reading your post on DS tumor suppression…thanks for stopping by!

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