Rethinking the way a tumor creates its blood supply is providing Augusta University researchers with a unique and patented target that could lead to a better way to choking off tumors.
Dr. Lan Ko’s lab is one of only three in the world that is targeting the protein GT198, whose gene Ko patented after she identified it in earlier work, and hers is the only one studying it for its potential to thwart the way tumors create their own blood supplies, a necessary step for tumor survival and growth.
Researchers have been trying for decades to find ways to effectively cut off the tumor blood supply, with sometimes undue optimism and plenty of controversy. The formation of new blood vessels is called angiogenesis and it is normally used to repair the body, but tumors also use it to flourish and the therapy to thwart it is called antiangiogenesis. The most famous of those therapies was developed by Dr. Judah Folkman at Harvard Medical School and prompted a New York Times headline in 1998 that cancer would soon be cured. Unfortunately, the drugs’ success in mice did not play out in people and antiangiogenesis drugs in cancer, like Avastin, have shown only modest improvements for patients.
That could be because they were thinking about how the tumor creates the blood supply in the wrong way, said Dr. Ali S. Arbab, a tumor angiogenesis expert at Georgia Cancer Center who is collaborating with Ko, a cancer biologist in the Department of Pathology at Medical College of Georgia at AU. Researchers in the past focused almost exclusively on endothelial cells, the cells lining blood vessels and on blocking their growth factors, Arbab said. But the reason it didn’t work is there are secondary forces at work, he said. Blocking the blood supply creates hypoxia, a lack of oxygen, that actually stimulates a stem-cell like function of tumors cells to transform themselves into blood vessels, Arbab said.
“We call this vascular mimicry,” he said. Those tumor cells can also create a type of blood vessel cell called a pericyte, a smooth-muscle-like cell that wraps around endothelial cells to form blood vessels, which in turn can become tumors.
In a study by Ko and Arbab and others published as an Advanced Publication in the journal Oncotarget, they show that malignant forms of pericytes can become a chicken and egg argument for tumor formation and also show a new way of thinking about how tumors form and how tumors form blood vessels.
“The newer idea is that the tumor can form the blood vessel by itself. And now we go one step further saying essentially there are stem cells on the (blood) vessel and those stem cells by themselves can form a tumor,” Ko said. The GT198 is an oncoprotein, or cancer-inducing protein, that causes those stem cells to form malignant pericytes that could then form a malignant blood vessel and tumor, she said.
“Before you have a tumor, you have an altered blood vessel and that blood vessel can form a tumor, then that’s where the tumor comes from,” Ko said. They found this protein abundantly in a rat model using human cells from a nasty brain tumor called glioblastoma multiforme, and also in human oral cancer patient samples.
“This is probably true for many tumors, not just brain tumors and oral cancer,” Ko said. “It could be a common mechanism for multiple tumors. We have to demonstrate it even more. This is just the first report of this phenomenon.”
Mice with the brain cancer who were inoculated with the protein survived longer, which points the way to possibly use it as a therapy, perhaps as a monoclonal antibody that targets the GT198 protein, she said. In her earlier work, Ko cloned the gene responsible for the protein and “she is the patent holder,” Arbab said. The protein is much more highly expressed in cancerous cells than normal ones, Ko said.
“Normal pericytes don’t express a lot of this protein, only the bad ones express this protein,” she said. “If we really target against this protein, we can more or less specifically target the (malignant) ones. This could be a new target that was previously unrecognized.”
In unpublished work, they have found a current chemotherapy drug does inhibit the protein but not very well, Ko said.
“That is why we want to develop some better drugs,” she said.
Reach Tom Corwin at (706) 823-3213