It has long been known that people with trisomy 21 (Down syndrome) have a significantly lower risk of developing certain types cancers than the general public. Now researchers from Children’s Hospital Boston have discovered that genes found on the extra chromosome 21 may have something to do with it.
Publishing online May 20 in the journal Nature, cancer researcher Sandra Ryeom, PhD, and colleagues from Children’s Vascular Biology Program show that a single extra copy of Dscr1 (one of the 231 genes on chromosome 21 affected by trisomy, with three copies rather than two) is sufficient to significantly suppress angiogenesis and tumor growth in mice, as well as angiogenesis in human cells. The team also found its protein, DSCR1, to be elevated in tissues from people with Down syndrome and in a mouse model of the disease.
Further study confirmed that DSCR1 acts by suppressing signaling by the angiogenesis-promoting protein vascular endothelial growth factor (VEGF). In a mouse model of Down syndrome, endothelial cells (which make up blood vessel walls) showed a decreased growth response to VEGF when they had an extra copy of Dscr1. An extra copy of another chromosome 21 gene, Dyrk1A, also appeared to decrease cells’ response to VEGF.
Finally, Ryeom and colleagues showed that these extra genes suppress VEGF signaling via a specific signaling pathway inside endothelial cells–the calcineurin pathway. Until now, Ryeom says, little has been known about the internal pathways VEGF activates once it binds to cellular receptors; most existing anti-VEGF drugs work by simply binding to VEGF (like Avastin) or blocking its ability to bind to its cellular receptors.
"We’re now moving further downstream by going inside the cell," Ryeom says. "When we targeted calcineurin, we suppressed the ability of endothelial cells to grow and form vessels. While it’s likely not the only pathway that’s involved, if you take it out, VEGF is only half as effective."
Ryeom and her group next validated the mouse findings in human cells. In collaboration with George Daley, MD, PhD, and colleagues in the Stem Cell program at Children’s, she worked with induced pluripotent stem cells (iPS cells) created from skin cells from a patient with Down syndrome–one of 10 disease-specific lines recently developed in Daley’s lab.
Knowing that iPS cells tend to induce tumors known as teratomas when inserted into mice, Ryeom guessed that teratomas grown from iPS cells with an extra chromosome 21 would have far fewer blood vessels than teratomas from iPS cells with the normal number of chromosomes. She was right: blood vessels budded in the Down teratomas, but never fully formed.
Official statement by Children’s Hospital Boston: Why Do People with Down Syndrome Have Less Cancer?
Abstract in Nature: Down’s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1
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Image: The tumor on the top was spawned by stem cells derived from an individual with Down syndrome. It has a substantially smaller network of blood vessels (red) than the tumor on the bottom, which was generated by stem cells derived from a chromosomally normal individual.