Missing Link in Glioblastoma Pathway Identified

New research from the laboratory of Jennifer Yu, MD, PhD, Department of Stem Cell Biology and Regenerative Medicine, may be the first step in developing much-needed treatments for patients with glioblastoma—a fast-growing and aggressive form of brain cancer.

A key characteristic of glioblastoma is regions of low oxygen levels, called tumor hypoxia. As tumors enlarge, they outgrow their blood supply, making it difficult for tumor cells to get enough oxygen and changing the cellular microenvironment. For reasons that are not yet clear, hypoxic tumors are more resistant to traditional therapies like radiation and chemotherapy, which leads to poorer patient outcomes.

One hypothesis for the relationship between hypoxia and tumor resiliency is that low oxygen levels promote the growth of glioblastoma stem cells, a subset of tumor cells that are very aggressive and resistant to therapy. Dr. Yu and her collaborators set out to identify the missing link between hypoxia, a pro-cancer cell signaling pathway called Notch and glioblastoma stem cells.  

The team first studied human glioma samples from a tissue database to identify candidate proteins that might be involved in this pathway. They found that a protein called Vasorin—known to be induced in low-oxygen settings—was abundant in patients with aggressive brain cancers who had less favorable prognoses and poorer survival.

Next they studied Vasorin in cell culture to determine how it affects glioblastoma progression. Under normal conditions, an adaptor protein binds to and inhibits the pro-cancer Notch pathway (important for cell proliferation, differentiation and survival). They found that in a hypoxic environment, however, the abnormally abundant Vasorin instead binds to and switches on the Notch signaling pathway in glioblastoma stem cells, leading to unchecked tumor growth.

The team tested this theory in a preclinical model and showed that blocking Vasorin in mice led to reduced Notch signaling and longer survival.

These new findings, published in Cell Stem Cell, suggest that Vasorin is a viable target for the development of new treatment options to combat brain cancer. "Killing glioblastoma stem cells is key to curing brain tumors," Dr. Yu said. "More studies are needed, but perhaps inhibiting Vasorin can be used in conjunction with radiation therapy or chemotherapy in the future."

Dr. Yu also holds appointments in the Lerner Research Institute, Taussig Cancer Institute and Neurological Institute of Cleveland Clinic.

This study was supported by a NIH Clinical & Translational Science Award/KL2 Scholars Program, the National Cancer Institute and National Institute of Neurological Disorders and Stroke at NIH; The National Science Foundation of China; and the Cleveland Clinic Foundation.