For decades scientists have known that people with Down syndrome, who have an extra copy of chromosome 21, get certain types of cancer at dramatically lower rates than normal. Now, partly by using stem cells derived from the skin of an individual with Down syndrome, researchers at Children’s Hospital Boston have pinpointed the gene that appears to underlie the cancer-protective effect.

The researchers say the results of their study, which were published today in Nature, may point to a promising new target for future cancer treatments. And according to stem-cell biologists, the work also highlights a growing trend in the field: harnessing disease-specific stem cells not as therapies but rather as models for understanding particular genetic disorders.

Stem cells “can be useful not simply because you take them and transplant them,” says Evan Snyder, director of the stem cells and regenerative medicine program at the Burnham Institute for Medical Research in San Diego. “They are useful as models of disease that reveal other kinds of therapies.” Snyder was not involved in the new study.

The late Judah Folkman, a cancer researcher renowned for pioneering the notion that blocking angiogenesis–the growth of new blood vessels–can prevent tumors from thriving, hypothesized that the lower cancer rates associated with Down syndrome might be traced to anti-angiogenesis genes on the 21st chromosome. So Sandra Ryeom, a member of the Folkman Laboratory in the Vascular Biology Program at Children’s Hospital, zeroed in on a region on chromosome 21 known to encode a regulator of blood vessel growth called DSCR1.

In chromosomally normal mice, the standard two copies of the Dscr1 gene produce just enough protein to help reign in normal blood-vessel growth, but not enough to stem the angiogenesis overload triggered by a developing tumor. But in mice with an artificial version of Down syndrome (and thus a third copy of the Dscr1 gene), Ryeom found that the surplus of DSCR1 protein kept abnormal angiogenesis–and the resulting tumor proliferation–in check.

While Ryeom and her colleagues suspect that DSCR1 works in concert with a handful of other chromosome 21 genes, they confirmed that the protein plays a central role in tumor suppression. A third copy of the Dscr1 gene alone was enough to stifle cancer formation in otherwise normal mice, though not to the same degree as in the Down syndrome mice.

To confirm that the gene is relevant in human cancers, Ryeom and her colleagues created a custom line of stem cells from skin cells taken from an individual with Down syndrome. Using a relatively new technique called induced pluripotent stem (iPS) cell reprogramming, researchers can express specific genes in differentiated adult cells and revert them to an earlier developmental state, where they are capable of giving rise to many different cell types.

Human iPS cells offer a convenient means to study cancer growth. Injected into mice with compromised immune systems, they generate chaotic but benign tumors composed of many kinds of tissue. When the researchers injected iPS cells derived from a chromosomally normal individual, the resulting tumors spawned elaborate networks of blood vessels to feed themselves. But when Ryeom’s team injected iPS cells derived from a Down syndrome patient, the tumors formed hardly any blood vessels at all.

In addition, the stem cell approach could allow the researchers to zero in on other potential anti-angiogenic proteins on chromosome 21 by tweaking gene copy numbers in the iPS cells. “We basically can map which genes are necessary in human Down syndrome cells to block blood-vessel growth,” says Ryeom. The iPS cells could also be used to test potential DSCR1-like drugs.

“The idea of being able to combine a mouse model of disease with actual human cells in culture is very attractive,” says Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute in La Jolla, CA, who was not involved in the research. “It’s a really big step forward.”

Now that Ryeom and her colleagues have shown the importance of the DSCR1 pathway in blocking tumors, the researchers are testing it as a potential target for cancer drugs. By chopping the protein into tiny pieces, they have identified the smallest chunk required to interfere with abnormal blood-vessel growth. Ryeom envisions using that chunk not just as a treatment for cancer, but also perhaps as a prophylactic.”If we could take this as sort of a preventative, vitamin-like therapy,” she speculates, “would it block all of us from having tumor cells grow into these huge, lethal masses?”

Debabrata Mukhopadhyay, a professor of biochemistry and molecular biology at the Mayo Clinic Cancer Center in Rochester, MN, advises caution. He says that because the role of DSCR1 in normal development isn’t yet well understood, toying with its biological pathway might have unintended consequences. He is optimistic, though, that the new study will help researchers begin to decipher that mechanism.

“If there is any distinct difference between DSCR1’s effect on pathological versus physiological angiogenesis, that needs to be resolved,” says Mukhopadhyay. “But this is a very important way of looking for anti-angiogenic therapy.”