A set of genes linked to certain health problems in people with Down syndrome may also explain the longstanding question of why these patients have a lower-than-average rate of solid tumors. A new study in Scientific Reports examines this possible association using a model of early embryonic development comprised of differentiated cells from human pluripotent stem cells (hPSCs). The authors mapped out some of the genetic pathways affected in people with Downs. They suggest these genes might make useful drug targets for cancer prevention.
This work was led by scientists from Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago. The findings were published August 6, in Scientific Reports.
“Our promising preliminary data carries strong potential for ultimately developing gene-targeted therapies to inhibit solid tumor growth in the general population,” says co-lead author Yekaterina Galat, research associate at the Institute. “Our findings may also provide gene targets for therapies aimed at alleviating the clinical abnormalities in people with Down syndrome.”
Down syndrome is a congenital disorder caused by trisomy 21. It causes cognitive impairment, muscle hypotonia, heart defects, and other clinical anomalies. One interesting observation about these patients, however, is that besides having certain typical health problems, they also have a lower than average rate of solid tumors.
The Manne researchers wanted to know if Down-specific variations in early development might suppress or otherwise interfere with tumorigenesis and spread. They created a model of early development in Down using skin samples from two patients. From those they induced pluripotent stem cells that were then differentiated into endothelial cells, which build blood vessels and the vascular system, and mesodermal cells, which are responsible for connective tissues and muscle development.
This study showed that down-regulated genes appear to be involved in the abnormal muscle development and heart problems that are common in people with Down syndrome. Further, decreased expression of such genes interferes with solid tumor formation and growth. These genes were associated with impeded cell movement, slower proliferation, and reduced inflammatory response, which creates a microenvironment that is not conducive to solid tumors. The researchers followed up with genome-wide analyses using publicly available data from 11,000 patients.
Differentially expressed genes in mesodermal cells included cytoskeleton-related genes (actin and myosin), ECM genes (Collagens, Galectin-1, Fibronectin, Heparan Sulfate, LOX, FAK1), cell cycle genes (USP16, S1P complexes), and DNA damage repair genes. For endothelial cells, most down-regulated genes were associated with cellular response to external stimuli, cell migration, and immune response (inflammation-based). The authors say that together with functional assays, these results suggest impaired mesodermal development capacity during early stages, which likely translates into connective tissue impairment.
“When we performed genomic analyses comparing mesodermal and endothelial cell lines, we were surprised to find that trisomy 21 impacted gene expression across the entire genome. Furthermore, the decreased expression of the genes we studied was consistent, and the large extent of their down-regulation was notable as well,” says co-lead author Mariana Perepitchka, research associate at the Manne Research Institute at Lurie Children’s. “This significant down-regulation potentially creates conditions that are opposite of what solid tumors would need to take hold. So, in a way, Down syndrome provides us with a non-traditional lens to study cancer development.”
Overall, their work shows that trisomy 21 impacts many biochemical pathways across the genome, some of which may contribute toward promoting tumor resistance.
“We still need to validate our findings in an animal model,” says senior author Vasil Galat, PhD, Director of Human iPS and Stem Cell Core at Manne Research Institute at Lurie Children’s and research assistant professor of pathology at Northwestern University Feinberg School of Medicine. “The potential for gene-targeted therapies is very exciting, especially since it could help individuals born with Down syndrome and the general population battling cancer.”
