A study led by investigators from Massachusetts General Hospital (MGH) and the University of Cyprus reveals details of a way the dangerous brain tumors called glioblastomas resist the effects of antiangiogenic drugs designed to cut off their blood supply. In their report published in PNAS, the researchers describe how the tumors can spread along existing blood vessels in normal tissue, a process called vessel co-option that can lead to compression of those vessels, reducing the oxygen supply to adjacent tissues and actually stimulating angiogenesis.

“The treatments designed to starve tumors by pruning away blood vessels have provided little or no survival benefits to patients with glioblastoma, says Rakesh K. Jain, PhD, director of the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology and senior author of the PNAS report. “Because of its ability to circumvent a tumor’s need to develop a new blood supply, vessel co-option can confer resistance to antiangiogenic therapy. Unfortunately this mode of tumor progression is difficult to target because the underlying mechanisms are not fully understood.”

To get a better understanding of how cancer cells interact with the vasculature during co-option, Jain and his team followed tumor progression in mouse models of glioblastoma. Using advanced imaging technology they found that treating existing glioblastomas with the antiangiogenic drug cediranib increased the spread of tumor cells along existing blood vessels and away from the primary tumor mass. They also presented evidence that this process causes the compression of co-opted vessels by tumor cells, which can trigger hypoxia-induced angiogenesis.

Dynamics of blood vessel co-option by brain tumors
Glioblastomas can maintain a nutrient supply despite the use of antiangiogenic drugs by co-opting existing blood vessels. A treatment strategy targeting both angiogenesis and vessel co-option may produce better results. (Chrysovalantis Voutouri, PhD, University of Cyprus)

Using the data from these experiments and from previous studies, the investigators developed a mathematical model that takes into account the biological and physical events driving the process of tumor growth and response to antiangiogenic treatment – from the earliest stages of vascular modification, through vessel co-option to secondary angiogenesis. Designed to integrate events from the cellular and subcellular levels with overall tumor growth, the model’s predictions matched the results of several published studies of vessel co-option and further suggested that tumor progression can be more effectively inhibited by combination therapies that block both angiogenesis and co-option.

Jain notes that the possibility that glioblastoma progression can only be stopped by combination therapies has important clinical implications. A previous study from his team identified a specific pathway – the Wnt signaling pathway – as a regulator of vessel co-option in glioblastoma, suggesting that drugs inhibiting that pathway could block co-option. The new model also predicts that targeting co-option before using antiangiogenic drugs would be a better strategy than administering both drugs simultaneously.

“With a number of agents that block Wnt signaling in clinical trials, our work provides the rationale for testing the proposed combination for glioblastoma, a uniformly fatal disease,” says Jain, the Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School.

Triantafyllos Stylianopoulos, PhD, of the University of Cyprus is co-corresponding author of the PNAS paper. The co-lead authors are Chrysovalantis Voutouri, PhD, University of Cyprus, and Nathanial Kirkpatrick, Steele Labs. Additional co-authors are Euiheon Chung, Lance Munn, PhD, and Dai Fukumura, MD, PhD, Steele Labs; Fotios Mpekris, PhD, University of Cyprus, and James Baish, PhD, Bucknell University. Support for the study includes National Cancer Institute grants P01 CA080124, R01 CA126642, R01 CA115767, R01 CA096915, R01 CA085140, R01 CA098706, R35 CA197743, National Heart Lung and Blood Institute grant R01 HL128168; European Research Council grant 336839 and support from the National Foundation for Cancer Research, the Ludwig Center at Harvard and the Jane’s Trust Foundation.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."