Scientists have found that overexpression of a protein called Down Syndrome Critical Region 1 (DSCR-1) blocks the formation of new blood vessels and thus reduces tumor growth. Therapeutics based on this finding may potentially lead to new cancer treatments.
The research appears as the "Paper of the Week" in the November 26 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.
Many vascular disorders including atherosclerosis, tumor growth, and inflammation are caused by the activation and dysfunction of the endothelium. This layer of cells lines the inside of blood vessels and regulates many processes including new blood vessel formation, blood vessel diameter, blood clotting, the migration of circulating white blood cells, and the normal release of molecules involved in inflammation
"Because endothelial cells are so active, any perturbation in their function may have undesirable effects," explains Dr. Takashi Minami of the University of Tokyo. "Indeed, endothelial cell dysfunction underlies many disease states in humans, including--but certainly not limited to--stroke, coronary artery disease, cancer and preeclampsia. An important goal in vascular research is to develop new strategies that inhibit endothelial cell dysfunction and abnormal blood vessel formation."
Certain agonists, such as vascular endothelial growth factor and the serine protease thrombin, cause endothelial cells to increase their expression of genes involved in proliferation, inflammation, and thrombosis. Dr. Minami and his colleagues found that these agonists also turn on a gene that produces Down Syndrome Critical Region 1 (DSCR-1), and that DSCR-1 then negatively feeds back on the agonists and shuts off their production. Thus, DSCR-1 acts as a circuit breaker in agonist signaling, and serves in a negative feedback loop to inhibit endothelial cell activation and growth.
More importantly, Dr. Minami and his colleagues discovered that when DSCR-1 is overexpressed in mice, it blocks the formation of new blood vessels and thereby reduces tumor growth.
"It has long been recognized that patients with Down syndrome have reduced risk for developing solid tumors and atherosclerosis," notes Dr. Minami. "DSCR-1 may be expressed at higher levels in patients with Down syndrome. Based on the results of the current study, it is interesting to speculate that the DSCR-1 auto-inhibitory loop in endothelial cells is responsible--at least in part--for the reduced risk for tumors and atherosclerosis in this patient population."
This connection between overexpression of DSCR-1 and a reduced risk for solid tumors and inflammatory states such as atherosclerosis may eventually be used for therapeutic gain in non-Down syndrome patients. "The development of methods to overexpress DSCR-1 in the endothelium would provide a novel strategy for reducing blood vessel formation and thus tumor growth, and for dampening endothelial cell dysfunction," says Dr. Minami.