Angiogenesis, metastasis impacted by subtype in glioma

Blood vessels and angiogenesis, the growth of new blood vessels, play a key role in most cancer types. As the microenvironment of tumors is generally hypoxic—low on oxygen—tumors co-opt the vascular system around them to spur supporting blood vessel growth and keep them supplied with oxygen and blood flow. However, such blood vessels are generally “leaky,” with weak vessel walls, which allows tumor cells to slip through and migrate throughout the body.

A multi-center team explored the interaction between tumor cells and blood vessels in glioma recently, and found that the type of glioma can affect how the cancer cells react with vasculature. The team consisted of researchers from Massachusetts General Hospital, the Department of Neuroscience at Genentech Inc., the University of California, San Francisco and the Department of Molecular Cell Biology at the Weizmann Institute of Science in Rehovot, Israel. Their study, “A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment,” was published online in Cancer Cell.

Gliomas, also known as intra-axial brain tumors, represent about 33 percent of all brain tumors, according to Johns Hopkins Medicine. Some of the main types of gliomas consist of astrocytomas (comprising nearly half of all primary brain tumors), ependymomas and oligodendrogliomas, which develop from astrocytes, ependymal cells and oliogodendrocytes, respectively. Glioblastomas, which also develop from astrocytes, also fall into the category of gliomas, and represent one of the deadliest and fastest-spreading cancer types.

Astrocytes are connective tissues cells, and astrocytomas are generally found in the cerebrum, though they can also appear in the cerebellum. Ependymal cells line the ventricles or spinal cord, and as such these tumors are most often found near the cerebellum, though they can metastasize to other locations in the brain as tumor cells follow the path of spinal fluid, according to the Johns Hopkins Medicine Health Library website. As for oligodendrocytes, these are supportive tissue cells of the brain, and oligodendrogliomas generally appear in the cerebrum, “a better prognosis than most other gliomas,” the website notes.

“Despite massive basic and clinical research efforts, the treatment of glioblastoma and other malignant gliomas remains one of the most challenging tasks in clinical oncology,” commented Dr. Rakesh Jain, director of the Edwin L. Steele Laboratories for Tumor Biology in the Massachusetts General Hospital (MGH) Department of Radiation Oncology and co-senior author of the report. “Glioblastomas are highly vascularized and interact closely with pre-existing blood vessels for oxygen and nutrients. They also contain a very diverse population of cells, with characteristics of stem cell and other cells found within the brain, and may use different strategies to recruit or access blood vessels, depending on the local microenvironment and on treatments that are applied.”

One of the ways by which gliomas can migrate through the brain is “co-option,” wherein single cancer cells migrate via blood vessels or as dense clusters that then trigger angiogenesis, or the development of new blood vessels. In this work, the research team focused on vascular development and oligodendrocytes—in particular, their work centered on a protein known as Olig2, which is expressed in most glioma subtypes and plays a role in the development of oligodendrocytes.

Oligodendrocyte precursors (OPCs) expressing Olig2 can give birth to gliomas, and within these cells, the Wnt7 protein is part of embryonic vascular development in the brain, including how the cells migrate along blood vessels. As the research team studied the connection further, they found that Olig2-positive glioma cells can migrate via single-cell co-option without damaging blood vessels, though the cells capable of doing so present with increased expression of Wnt7. When Olig2-positive cells expressing Wnt7 were treated with drugs that inhibit Wnt7 (or another protein in the Wnt pathway), glioma cells lost contact with blood vessels, instead creating cell clusters seen in Olig2-negative gliomas, as reported in an MGH press release.

Olig2-negative cells, by contrast, develop as clusters of cells around vasculature, and are larger and denser. These cells express high levels of VEGF, an angiogenic factor, and Olig2-negative gliomas increase the activation of innate immune cells, resulting in inflammation, and break down the blood-brain barrier. When glioma cell lines were treated with a VEGF inhibitor, single-cell vascular co-option was increased, which was theorized to be due to increased expression of Olig2.

“These findings have significant therapeutic implications for our understanding of heterogeneity in glioma and how tumor components exploit alternative strategies to interact successfully with the vasculature despite anti-angiogenic treatment,” said Dr. David Rowitch of UCSF and the University of Cambridge in the U.K., co-senior author of the study. “Our identification of the Olig2/Wnt7 vessel co-option pathway reveals a potential target for future combination therapies.”

Rowitch and his lab are also pursuing astrocytes and oligodendrocytes in related research, according to his faculty page on the UCSF website. In one project, “Oligodendrocyte Lineage Gene Function in the CNS,” the team “will test the hypothesis that diverse neurogenic and gliogenic functions of Olig2 are regulated by phosphorylation. We are further defining the role of Olig2 protein expression and post-translational modification in glioma, and specific roles downstream of BRAF and SHH signaling.” In another project, “Cellular and Genetic Origins of Astrocytes,” the focus is “to identify a set of genetic markers for development of astrocytes and to map their cellular origins in the central nervous system. The hypothesis to be tested is that astrocytes develop from heterogeneous locations and might have diversified functions in various regions of the CNS.”