How Down syndrome works against cancer

Extra dose of protein limits blood vessel formation that tumors need

Surplus production of a cancer-suppressing protein may explain in part why people with Down syndrome seldom get cancer, a study in the May 21 Nature shows.

People born with Down syndrome have an extra copy of chromosome 21, instead of the usual two copies — one from each parent. The third chromosome causes genetic aberrations that result in the mental retardation and telltale physical traits that define the condition.

But chromosome 21 carries 231 genes, including some that may well suppress cancer. In the new study, researchers provide evidence that the protein encoded by the RCAN1 gene reins in the rampant blood vessel growth that a tumor needs to thrive. Scientists theorized that having an extra copy of the gene would result in more protein being made and add to an anticancer effect.

Scientists have long suspected that such genetic benefits might accrue from having an extra chromosome 21. A recent study found that people with Down syndrome are only about one-tenth as likely to get a solid-tumor cancer as are people without the syndrome.

A tumor needs veins and arteries to nourish its rapid growth. So tumors fashion a haphazard cluster of new vessels that mimic a legitimate body process called angiogenesis. The late Judah Folkman of Harvard Medical School in Boston saw angiogenesis as the Achilles’ heel of tumors and suspected that cancer suppression in people with Down syndrome could stem from extra copies of propitious genes on chromosome 21 that thwart angiogenesis.

In the new study, Folkman’s colleagues tested the antitumor effect of RCAN1, alsocalled DSCR1. The researchers compared two sets of mice, some with a third copy of the RCAN1 gene and some with the usual pair. When the mice were surgically implanted with melanoma or lung tumors, animals making the additional RCAN1 protein had less than half as much tumor growth and substantially fewer blood vessels around those tumors as did mice with a normal RCAN1 complement.

Tests on human fetal tissues also showed that Down fetal tissues had nearly twice as much protein encoded by RCAN1 as did normal tissues.

The RCAN1 protein dampens vessel growth by inhibiting the actions of vascular endothelial growth factor, preventing it from instigating a cascade of vessel-growth orders, says study coauthor Sandra Ryeom, a cell biologist at Harvard Medical School and Children’s Hospital in Boston.

Ryeom and her colleagues report that another chromosome 21 gene, called DYRK1A, also encodes a protein that can subvert this chain of events.

“This is a very interesting study,” says Kelvin Davies, a biochemist at the University of Southern California in Los Angeles.

Davies’ lab has found that people with the movement disorder Huntington’s disease have a shortage in the brain of RCAN1-1L , a form of RCAN1. That finding suggests that increasing RCAN-1L activity might ease the condition, he and his colleagues report in the May 1 Journal of Biological Chemistry. Also, Davies’ team reported in 2007 that brain cells of people with Alzheimer’s disease have too much RCAN1-1L activity, he says, suggesting that gene may be implicated in that disease.

“It seems we can now add cancer to the growing list of ailments in which RCAN1 is integrally involved,” Davies says.

Perhaps the best-known gene found on chromosome 21 is Endostatin, which also thwarts angiogenesis. Folkman saw Endostatin as a potential anticancer weapon, and a drug derived from its protein is currently being tested in cancer patients.

Meanwhile, another gene on chromosome 21 called ETS2 encodes a protein that seems to hinder cancer by other means. Its role is still being deciphered, says Roger Reeves, a geneticist at Johns Hopkins University School of Medicine in Baltimore.

“Chromosome 21 appears to contain a variety of genes that, when over-expressed, inhibit the growth of tumors,” Reeves says. Ultimately, the best therapeutic approach might be a cocktail of drugs derived from the proteins encoded by these genes, he says.

The RCAN1 gene is activated in a variety of cells, Ryeom says. A drug derived from its protein would work best if it specifically targeted the blood vessel cells called endothelial cells, she says. “We would be putting a tag on it, like a zip code, that sends it directly to the surface of endothelial cells,” she says.

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