COLUMBUS, Ohio – New research shows how the tumors caused by an incurable form of brain cancer develop blood vessels. The research shows that the tumors attract stem cells that are circulating in the blood, as well as co-opting blood vessels from the brain itself.
The animal study found that in gliomas, about 75 percent of new blood vessels in the tumor come from the surrounding brain, but that about 25 percent come from progenitor cells that originate in the bone marrow and are carried in the blood.
The research also shows that the progenitor cells are drawn to the tumor because the cancer cells release a substance called stromal-derived factor-1 (SDF-1), a chemical released by some cells to attract certain other cells.
E. Antonio Chiocca, M.D., Ph.D.
The study provides new insights into the process of blood-vessel growth in human brain tumors called gliobastomas. The appearance of new blood vessels signals that the cancer has advanced to its most dangerous stage, called gliobastoma multiforme, which is characterized by rapid tumor growth. Patients with gliobastoma multiforme survive about one year on average.
“These findings indicate that blocking blood-vessel growth in tumors will probably require multiple drugs, some that inhibit the growth of blood vessels coming from the surrounding brain and are co-opted into the tumor, and some that inhibit blood vessels that form from endothelial progenitor cells,” says principal investigator Dr. E. Antonio Chiocca, professor of neurological surgery and co-director Ohio State University’s Dardinger Center for Neuro-oncology.
The research, published online Sept. 15 in the journal Cancer Research, was largely done while Chiocca was at Massachusetts General Hospital and Harvard Medical School and in collaboration with David T. Scadden. The scientists who performed the work were Dr. Manish Aghi and Ken Cohen at Harvard.
To learn whether glioblastoma blood-vessel cells come from the brain or from progenitor cells, the researchers used two sets of mice. In one set, Aghi and Cohen engineered a marker protein that fluoresced green into the animals’ bone marrow cells, which causes them to glow green. These cells were then transplanted into the second set of mice, in which the bone marrow was destroyed. (Bone-marrow cells include blood-vessel progenitor cells.)
A few weeks later, Aghi and Cohen implanted mouse glioma cells into the animals’ brains and under the skin. As the tumors grew, blood vessels that developed from progenitor cells contained the green marker, while those that developed from the brain did not.
To determine if SDF-1 made by the glioma cells attract the blood-vessel progenitor cells to the tumor site, the researchers implanted cells from a glioma cell line that did not make the substance. These tumors contained no blood vessels made from progenitor cells.
The researchers then repeated this experiment, but engineered the glioma cells in a way that caused them to make the substance. These tumors did contain blood vessels formed from progenitor cells.
“This finding shows that if the tumor doesn’t make SDF-1, the progenitor cells won’t travel to it,” Chiocca says. “It also explains why other studies sometimes didn’t find progenitor cells.They used glioma cell lines that don’t make SDF-1.”
The research also clarified another controversy. Some earlier studies have shown that progenitor cells sometimes become cells that form the walls of the blood vessels themselves, while at other times they become smooth-muscle cells that surround the vessels.
“We found that it depends on where the experimental glioma is located,” Chiocca says. “If we implant a glioma in the brain, progenitor cells form blood-vessel cells. But it is implanted under the skin, they form smooth-muscle cells. The local microenvironment dictates what the progenitor cells will become.”
Chiocca speculated about why tumors might build blood vessels using progenitor cells. “It might be a faster way for tumors to make the new blood vessels they need to support their rapid growth.”
Funding from the National Cancer Institute, the National Brain Tumor Foundation and the Neurofibromatosis Foundation supported this research.
Chiocca is also the Dardinger Family Professor of Neurological Surgery, chairman of OSU’s Department of Neurological Surgery and co-leader of the OSU Comprehensive Cancer Center Viral Oncogenesis Program.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of the nation’s leading centers for research on the prevention, detection, diagnosis and treatment of cancer. The OSU CCC – James encompasses seven interdisciplinary research programs and includes more than 200 investigators who generate over $100 million annually in external funding. It is a founding member of the National Comprehensive Cancer Network, and OSU’s James Cancer Hospital is consistently ranked by U.S. News & World Report as one of America’s best cancer hospitals.# # #
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