Researchers at Uppsala University, in collaboration with colleagues in Sweden, Norway, Finland, and Germany, have identified an entirely new mechanism by which the body inhibits the formation of abnormal new blood vessels. The discovery could lead to new treatments for cancer and other diseases that are dependent upon angiogenesis. Already, there a number of approved antiangiogenic drugs that have dramatically improved the treatment outlook for some patients with several common and deadly cancer types.
The new study investigated the function of a protein called histidine-rich glycoprotein (HRG) that is naturally is present in blood plasma circulating throughout the body. Previous studies in mice have shown that HRG inhibits angiogenesis and tumor growth. The new study demonstrated, among other things, that the HRG fragment responsible for the inhibitory effect is present in human tissue, which suggests that it is part of the body’s own defense system against abnormal angiogenesis, as may occur in cancer.
“Current antiangiogenic medications for cancer work in a similar way, by influencing the function of one of the agents that promotes angiogenesis,” said research fellow Anna-Karin Olsson of the Department of Medical Biochemistry and Microbiology at Uppsala University, who headed the study. “A problem with the medications is that the body develops resistance to them as treatment progresses.”
The HRG fragment inhibits angiogenesis by binding to endothelial cells, which comprise blood vessels. Analysis of a large number of human tissue samples showed that the HRG fragment binds to blood vessels in cancer patients but not in healthy persons. The study also showed that the HRG fragment binds to blood vessels in the presence of activated platelets, blood cells that limit bleeding in the event of injury. This finding is particularly interesting, since cancer patients often exhibit high levels of platelet activation, and because platelets contain signals reflecting the body’s state of angiogenesis.
“Our findings suggest that attempting to inhibit angiogenesis is an aspect of the body’s own reaction to diseases like cancer,” says Anna-Karin Olsson. “The activated platelets create a microenvironment in which the HRG fragment is able to function as an angiogenesis inhibitor.”
Data from so-called “knockout” mice, whose bodies cannot manufacture HRG, support this conclusion. The mice are healthy and fertile, but exhibit high levels of angiogenesis in connection with tumor growth. This finding is consistent with the hypothesis that the mice lack an angiogenesis inhibitor.
“Our data describes an entirely new mechanism of action for an endogenous angiogenesis inhibitor,” says Anna-Karin Olsson. “This knowledge may eventually help in developing new, more effective drugs for inhibiting angiogenesis during disease treatment without affecting healthy vessels.”