People affected by Down syndrome rarely develop cancer. In fact, the overall cancer mortality in people with Down syndrome is less than 10 percent of that in the general population. Until recently, the explanation for this remained unknown.

“The body is packed with naturally occurring inhibitors of angiogenesis,” says Dr. William W. Li, President and Medical Director of the Angiogenesis Foundation. “So, observations like those in people with Down syndrome lead us to search for underlying biological reasons, such as the existence of elevated levels of molecules that inhibit blood vessel growth.”

The late cancer researcher Judah Folkman, M.D., pioneer of the angiogenesis field, theorized that the cancer protective effects in Down syndrome patients might reside on their extra copy of chromosome 21, the defect that causes Down itself, where there are three chromosome copes instead of two (trisomy). This chromosome contains genes that blocks angiogenesis, the development of blood vessels essential for tumor growth. Folkman’s interest in why patients with Down syndrome have such a reduced risk for cancer focused on endostatin, an anti-angiogenic compound produced in the body. Discovered in the Folkman lab, endostatin is a fragment of collagen 18—whose gene is also on chromosome 21. People with Down syndrome have almost doubled levels of endostatin because of the extra copy of the gene.

A new study by Sandra Ryeom, Ph.D., and colleagues at Boston Children’s Hospital has now identified two other specific genes on chromosome 21 that suppress tumor angiogenesis. These genes are called DSCR1 and Dyrk1A.  Published online May 20th in the journal Nature, the Ryeom study shows that a single extra copy of DSCR1 (one of the 231 genes on chromosome 21) is sufficient to significantly suppress angiogenesis and tumor growth.

The researchers discovered that the protein, DSCR1, made by the gene is elevated in tissues from people with Down syndrome and in a mouse model of the disease. DSCR1 acts by suppressing signaling by the angiogenesis-promoting protein VEGF (vascular endothelial growth factor). In a mouse model of Down syndrome, the endothelial cells comprising the lining of blood vessels showed a decreased growth response to VEGF when they had an extra copy of DSCR1. An extra copy of a second gene on chromosome 21, Dyrk1A also decreased the cells’ response to VEGF.  Drug treatments that target VEGF, such as bevacizumab (Avastin), sorafenib (Nexavar), and sunitinib (Sutent), are effective in treating multiple cancers, including colon, breast, lung, kidney, liver, and gastrointestinal stromal tumors (GIST).

Ryeom and colleagues defined the specific mechanism by which DSCR1 inhibits VEGF, through suppression of VEGF signaling via the calcineurin pathway in endothelial cells. One of the genes involved in this pathway is cyclooxygenease 2 (COX-2), which is an important mediator of the angiogenic response to VEGF. In mice with Down syndrome, their blood vessel cells showed a marked decrease in COX-2 expression, suggesting that a modest increase in DCR1 suppresses the expression of COX-2 and probably other VEGF-responsive targets.  COX-2 is the target of drugs such as celecoxib (Celebrex), which has also been shown to inhibit angiogenesis.

Most existing anti-VEGF drugs work by simply binding to circulating VEGF, or by 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 (in stimulating tumor angiogenesis).”

Ryeom and her group next validated the mouse findings in human tumor cells. In collaboration with George Daley, M.D., Ph.D. and colleagues in the Stem Cell Program at Children’s Hospital, she worked with induced pluripotent stem cells (iPS cells) created from skin cells from a human patient with Down syndrome—one of 10 disease-specific stem cell lines recently developed in Daley’s lab. Knowing that iPS cells induce tumors called teratomas when injected into mice, Ryeom hypothesized that teratomas grown from iPS cells, which have an extra copy of chromosome 21—and therefore the antiangiogenic gene DSCR1—would have far fewer blood vessels than expected. This proved correct: blood vessels in the Down’s patients’ teratomas never fully formed.

“Our studies helped validate and confirm the suppression of angiogenesis,” says Ryeom. “It suggests that these two genes—DSCR1 and Dyrk1A—might be new targets for cancer therapy.”

According to Dr. Li, the cancer protective mechanisms of naturally occurring angiogenesis inhibitors suggest promising avenues to develop cancer prevention strategies. “The emerging lesson,” he said, “is that we should look at ways to block abnormal angiogenesis as a way to prevent, and not only to treat, cancer.”