Down Syndrome Offers Fresh Clues to Angiogenesis
Authors: K. Rowan
Journal: JNCI Journal of the National Cancer Institute (2009)

People with Down syndrome, who have an extra copy of chromosome 21, rarely develop solid tumors, and researchers are starting to put together the pieces of this genetic puzzle to learn why. In a recent study led by Sandra Ryeom, Ph.D., a researcher at Children’s Hospital Boston, scientists identifi ed two genes on chromosome 21, known as DSCR1 and Dyrk1a, that may play crucial roles in inhibiting the growth of new blood vessels. Ryeom’s team found evidence that the single extra copy of DSCR1 present in the cells of people with Down syndrome suppresses angiogenesis — a crucial ingredient in tumor growth. “This was an absolutely fascinating study,” said Nancy Demore, M.D. , a surgical oncologist at the University of North Carolina, who worked in the late Judah Folkman’s lab in the 1990s. Folkman, who founded angiogenesis research, long suspected that one could fi nd clues to angiogenesis by studying Down syndrome, or trisomy 21, said Demore, who was not involved with this study. “He would talk about the fact that kids with Down syndrome had lower rates of solid tumors and hypothesized that this difference could be due to genes on chromosome 21. It’s fascinating to see a paper published in 2009 completely validating his hypothesis from then.” Antiangiogenesis research is currently booming, but according to Demore, Ryeom’s work differs from the scores of trials under way that are focused mainly on inhibiting vascular endothelial growth factor (VEGF) with monoclonal antibodies. “This is another way to go: to look at the factors that stimulate angiogenesis and try to block multiple angiogenic factors,” she said. The study revealed that the two genes both encode proteins that disrupt the calcineurin pathway, which is involved in angiogenesis. It also showed that, compared with control subjects, DSCR1 protein levels are increased in the tissues of people with Down syndrome and in Ts65Dn mice — the mouse model of Down syndrome that has three copies of 104 of the 231 genes on human chromosome 21. Further, the researchers compared the growth of two common tumors, Lewis lung carcinoma and B16F10 melanoma, in the Down syndrome mice and in control subjects. Growth of tumors was suppressed, and the density of microvessels was statistically signifi cantly lower in the Ts65Dn mice than in the diploid control mice. Also, when induced pluripotent stem cells derived from an individual with Down syndrome were injected into immunodefi cient mice, the tumors that grew had reduced mi crovessel densities — less angiogenesis — compared with those grown from induced pluripotent stem cells de rived from a person without Down syndrome. The next step was to fi nd a link between the suppressed angiogenesis and the extra copy of DSCR1. The DSCR1 gene was fi rst identifi ed in 1997 and was implicated in the signaling pathway of VEGF, a key pathway involved in angiogenesis, in 2004. But the gene’s role in angiogenesis was not well understood. “We took a different approach because not a lot was known about the intracellular pathways that inhibit blood vessel growth,” said Ryeom. VEGF is well studied, but the VEGF signal acts at the cell membrane, and the pathway she was interested in is downstream of the VEGF signal. To show that extra DSCR1 could inhibit angiogenesis, the researchers created a transgenic mouse with an extra copy of that gene only. In a normal cell, VEGF signaling activates calcineurin, which dephosphorylates a transcription factor known as nuclear factor of activated T cells (NFAT). NFAT then moves into the nucleus and the transcription of genes needed for angiogenesis begins. Ryeom’s team found that NFAT remained in the cytoplasm of cells with the extra DSCR1 gene, indicating that the calcineurin pathway was disrupted. When melanoma and carcinoma tumors were planted in the mice with the extra gene, the number of endothelial cells that line the blood vessels within the tumors was statistically