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Increased survival following tumorigenesis in Ts65Dn mice that model Down syndrome
1Department of Physiology and McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Abstract:
Epidemiologic results tend to suggest that adults with Down syndrome have a reduced incidence of cancer, but some studies have reached the opposite conclusion. In this study, we offer direct biological evidence in support of the notion that Down syndrome reduces incidence of multiple types of cancer. Previous studies showed that introduction of the Apc(Min) mutation into the Ts65Dn mouse model of Down syndrome by interbreeding caused formation of intestinal adenomas at a significantly reduced incidence compared with control (euploid) animals that did not have trisomy. To a large degree, this reduction was determined to reflect an increased dosage of the Ets2 tumor repressor gene due to trisomy. Studies of tumor grafts using Ts65Dn suggested angiogenesis as a mechanism that mediated reduced tumor growth, metastasis, and mortality in individuals with Down syndrome. To confirm and extend these findings, we employed the complex cancer mouse model NPcis, which is heterozygous for the Trp53 and Nf1 genes and through LOH develops lymphomas, sarcomas, or carcinomas with 100% penetrance. In this aggressive model, trisomy did not prevent cancer, but it nevertheless extended host survival relative to euploid littermates. However, protection in this case was not attributable to either Ets2 dosage or to reduced angiogenesis. Together, our findings indicate that the genetic complexity underlying Down syndrome supports multiple mechanisms that contribute to reduced mortality from cancer.
Insights
Down syndrome appears to reduce cancer incidence and mortality through multiple biological mechanisms. Trisomy influences tumor suppressor genes and angiogenesis, offering protection against various cancers.
Area of Science:
- Genetics
- Cancer Biology
- Developmental Biology
Background:
- Epidemiologic studies suggest a reduced cancer incidence in adults with Down syndrome, though findings are inconsistent.
- Previous research indicated trisomy in Down syndrome models may reduce intestinal adenomas via Ets2 gene dosage.
- Tumor graft studies in a Down syndrome mouse model suggested reduced angiogenesis contributes to lower cancer mortality.
Purpose of the Study:
- To provide direct biological evidence supporting the hypothesis that Down syndrome reduces cancer incidence.
- To investigate the role of trisomy in cancer development and mortality using a complex mouse model.
- To explore the underlying mechanisms, including gene dosage and angiogenesis, involved in cancer protection associated with Down syndrome.
Main Methods:
- Utilized the Ts65Dn mouse model of Down syndrome to study intestinal adenoma formation with the Apc(Min) mutation.
- Investigated the impact of trisomy on tumor growth, metastasis, and mortality using tumor grafts.
- Employed the NPcis mouse model, which is heterozygous for Trp53 and Nf1, to assess cancer development and survival in the context of Down syndrome trisomy.
Main Results:
- Trisomy in the Ts65Dn model significantly reduced intestinal adenoma formation, largely attributed to increased Ets2 tumor repressor gene dosage.
- Tumor grafts in Ts65Dn mice showed reduced growth, metastasis, and mortality, suggesting a role for angiogenesis.
- In the aggressive NPcis model, trisomy did not prevent cancer but extended host survival, independent of Ets2 dosage or reduced angiogenesis.
Conclusions:
- Down syndrome is associated with reduced cancer incidence and mortality through diverse biological mechanisms.
- Trisomy influences key cancer-related genes and processes, contributing to a protective effect against tumorigenesis.
- The genetic complexity of Down syndrome confers multifaceted protection against cancer, impacting host survival.
