Genetic Clue in Down Syndrome May Help Cancer Research

Down syndrome (DS) is a chromosomal disorder caused by an error in cell division that results in an additional third chromosome 21. People with DS face a marked increase for certain birth defects, such as congenital heart defect, and health conditions including hearing loss, respiratory and vision problems, thyroid disease, certain kidney disorders, and Alzheimer’s disease. And though they also have a 20-times greater chance for leukemia, people with DS have just 10 percent the risk than that of the general public of dying from many common solid-tumor cancers, including brain, lung, breast, colon, pancreas, and bone cancers—a phenomenon researchers have theorized could be due to the additional chromosomal material but have been unable to fully explain—until now.

Building on work by Harvard University’s late Dr. Judah Folkman, Sandra Ryeom, a cell biologist at Harvard Medical School and Children’s Hospital in Boston, and colleagues used induced pluipotent stem cells or iPS cells from a volunteer with DS to genetically engineer mice to have a version of the condition. They found that the DS mice, as do people with DS, have a third copy of chromosome 21, which gives them extra versions of 231 different genes. Among them is DSCR1, also known as RCAN1, that in lab dish experiments was found to suppress vascular endothelial growth factor or VEGF—one of the compounds necessary for the process called angiogenesis. “This suggests that DSCR1 is incredibly important in blocking tumor growth, and the reason the tumors grow slowly is that blood vessel formation was blocked,” Ryeom said. “This told us that DSCR1 played a critical role in suppressing tumor angiogenesis.”

But Ryeom says DSCR1 alone is not sufficient for angiogenesis and that there may be as many as five genes involved in the action. In fact, she and her colleagues believe that DSCR1 works with another chromosome 21 gene, DYRK1A, to block what is known as the “calcineurin-signaling pathway”—which helps tumors develop the blood supply needed for their growth and survival. Without a blood supply to provide nutrients and oxygen, the tumors cannot “grow beyond a microscopic clump of cells,” 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.”

Dr. Gerald Feldman of the Wayne State University Center for Molecular Medicine and Genetics, calls the research promising, saying that stopping blood vessel formation not only starves the tumor, but stops metastasis, where the tumor cells enter the bloodstream and relocate somewhere else. “That’s the critical thing,” he said.

“We have known for some time that people with Down’s syndrome have lower incidences of cancer, apart from leukemia, than the rest of the population,” said Stuart Mills of the Down Syndrome Association. “This is one of the first studies to examine the reasons why, and we welcome its findings. We will be following further research with great interest.”

A variety of anti-angiogenic drugs are already used to treat cancer, the first of which, Avastin, was approved in 2004. But these medications are only showing marginal benefit and have side effects. Ryeom hopes to develop additional cancer therapies based on her research. “It is, perhaps, inspiring that the Down syndrome population provides us with new insight into mechanisms that regulate cancer growth and, by so doing, identifies potential targets for tumor prevention and therapy,” the researchers conclude.

Ryeom also envisions a low-dose anticancer drug that could be used as a preventative measure. “If we could take this as sort of a preventative, vitamin-like therapy, would it block all of us from having tumor cells grow into these huge, lethal masses?” she speculates. David Threadgill, a geneticist at North Carolina State University in Raleigh, says the idea makes good sense biologically, but there would be serious regulatory hurdles for any drug intended to be used before people develop cancer.

But Debabrata Mukhopadhyay, a professor of biochemistry and molecular biology at the Mayo Clinic Cancer Center in Rochester, Minnesota, advises an abundance of caution. He says that because DSCR1’s role in normal development isn’t yet well understood, tampering with its biological pathway could have unintended consequences. “If there is any distinct difference between DSCR1’s effect on pathological versus physiological angiogenesis, that needs to be resolved,” he said, but added that he is optimistic that the new findings will help researchers begin to decipher that mechanism. “But this is a very important way of looking for anti-angiogenic therapy.”