Research Reveals How Down Syndrome Shields Against Cancer

May 20 (HealthDay News) -- A pair of genes may explain why people with Down syndrome are largely spared from many types of cancer, Boston researchers report.

The same genetic mechanism could be a potent target for new anti-cancer therapies, said the scientists, who published their findings online May 20 in Nature.

The pressing question now becomes, when will this happen? Or will it happen at all?

"Most universities around the country are very good at finding targets for intervention in cancer and this study suggests that these two genes, if they were overexpressed in a tumor, could shut down the tumor blood vessels," explained Dr. Arthur E. Frankel, holder of the Tula Lee Stone Chair in Cancer Research at the Texas A&M Health Science Center College of Medicine.

"The problem is that's not such a trivial thing to do," added Frankel, who is also director of the Cancer Research Institute and of hematology/oncology with Scott & White. "The observation is true, but it's not immediately obvious to me that it's going to help anyone in the short term."

Individuals with Down syndrome, the most common genetic cause of mental retardation, carry an extra copy of chromosome 21 and, therefore, extra copies of each of the 231 genes found on that chromosome.

And while people with Down syndrome have an increased risk of developing certain types of leukemia compared to the general population, they have just 10 percent the risk of dying from many common solid-tumor cancers, including breast, brain, pancreas, lung and colon cancers.

The phenomenon has long been a scientific riddle.

"In the 1950s at Harvard Medical School, one of the exam questions was, 'Why don't people with Down Syndrome get cancer?' The answer then was because they don't live long enough," said study senior author Sandra Ryeom, a cancer researcher with the Children's Vascular Biology Program at Children's Hospital, Boston. "That's not true now. Many medical issues [for people with Down syndrome] are treatable and correctable, and they now live long enough. And we still find significant protection against solid-tumor cancers."

This study builds on the work of U.S. angiogenesis pioneer Dr. Judah Folkman, who died last year. Angiogenesis refers to the growth of blood vessels necessary to nourish cancer cells. Folkman hypothesized that angiogenesis inhibition might be key to preventing cancers from forming.

Folkman's initial theory stemmed partly from the observation that people with Down syndrome also suffered fewer angiogenesis-related diseases such as diabetic retinopathy, atherosclerosis and the eye disease macular degeneration.

These researchers zeroed in on the Dscr1 (Down syndrome candidate region-1) gene, which dampens the growth of blood vessels by inhibiting a chemical called vascular endothelial growth factor.

The gene's activity is elevated in mouse models of Down syndrome and in human Down syndrome tissue. This elevation in activity is enough to suppress tumors, although it doesn't explain the extent of the cancer-protective effect seen in individuals with Down's, the researchers said.

"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."

Dscr1 alone resulted in some tumor suppression but there may be as many as five genes involved in the action. "Dscr1 is necessary but not sufficient," Ryeom explained.

In fact, Ryeom and her colleagues believe that Dscr1 works with another gene on chromosome 21, called Dyrk1a, to block what's known as the "calcineurin-signaling pathway" -- a circuit involved in helping tumors develop the blood supply necessary to their growth and survival.

But the question remains: Will any of this information end up helping cancer patients?

"We now have some 10,000 targets for tumors but we sure don't have 10,000 anti-cancer drugs," Frankel pointed out. "We're trying to work with investigators to get drugs or proteins or nucleic acids that could then be used to try it out in patients, [but] the activity in that area is very, very little. Drug companies are very reluctant to try these new targets without simple approaches."

Another expert agreed that the road to any effective cancer therapy is an arduous and uncertain one.

"I think we need to study the field of angiogenesis but I also think it's pretty clear that targeting it and effectively manipulating it in patient disease, it's not the home run people thought it would be. It does help, and in some cases is pretty amazing but we're still learning where that's the case," said Dr. Jeffrey A. Toretsky, an associate professor in the departments of oncology and pediatrics at Georgetown University's Lombardi Cancer Center in Washington, D.C.

Take the example of Avastin, the prototypical anti-angiogenesis drug. "It's only showing a marginal benefit, and it has side effects," Toretsky said.

As for this contribution to the angiogenesis literature, he said that "the question I always pose is how could you plausibly think of manipulating this gene in a way that's technically possible today and not something to happen in the future. Otherwise this becomes something to think about, but you're going to have to think about the next step."

More information

There's more on Down syndrome at the U.S. National Institute of Child Health and Human Development.


SOURCES: Sandra Ryeom, Ph.D., cancer researcher, Children's Vascular Biology Program, Children's Hospital, Boston; Arthur E. Frankel, M.D., professor and Tula Lee Stone Chair in Cancer Research, Texas A&M Health Science Center College of Medicine, and director, Cancer Research Institute and hematology/oncology, Scott & White; Jeffrey A. Toretsky, M.D., associate professor, departments of oncology and pediatrics, Lombardi Comprehensive Cancer Center, Georgetwon University, Washington, D.C.; May 20, 2009, Nature, online

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