August 27, 2019
Written by: Carolyn Keating
Cancer. It’s never a word you want to hear when discussing your health or the health of a loved one. But brain cancer especially is a word you really hope doesn’t come out of your doctor’s mouth. While there are many different types of brain tumors, one of the worst is glioblastoma. This is the disease that took the lives of John McCain, Edward Kennedy, and Beau Biden. But what is glioblastoma, and why is it so deadly?
Glioblastoma is an aggressive and deadly brain cancer that grows very rapidly. It often starts out as a grade 4 tumor (the most serious kind) without any evidence of smaller, less dangerous tumors1. Perhaps even scarier is that doctors aren’t sure what puts people at risk for developing glioblastoma, other than previous head or brain radiation (from other cancer treatments, for example). It’s thought that these tumors come from a small group of stem or progenitor cells in the brain: cells that can produce neurons and other brain cells called glia, but that get hijacked into uncontrolled division and incorrect cell types. The tumors can grow anywhere in the brain, and depending on their location, people can experience different symptoms. For instance, patients with tumors in the front of the brain, where thinking and executive functions are controlled, may have mood and personality changes, whereas tumors around the brain areas that control speech can result in language deficits. Other symptoms are common regardless of the tumor’s location, such as headaches, seizures, and cognitive slowing. However, there is no typical pattern of symptoms; every patient reacts to glioblastoma differently2.
Treatment begins with first identifying that the patient has glioblastoma, which is done using MRI as well as analyzing tissue from the tumor itself. Once the tissue is confirmed to be a glioblastoma, as much of the tumor as possible is removed. Removal can be difficult though and some cells are often left behind, especially if the tumor is located next to brain regions that control important function like speech. The patient then usually receives chemotherapy as well as radiation therapy to try to destroy the remaining cells. Unfortunately, these current treatments aren’t very effective: only 5% of patients survive for 5 years after diagnosis, and that number drops to only 2% when patients are over 65 years old2.
Part of what makes glioblastoma so hard to treat is that the makeup of the tumors can be so different—both between patients, and within one single tumor. Research from earlier this month may shed light on what causes this diversity3. Scientists were able to analyze tumors from 20 adult and 8 pediatric glioblastoma patients. What sets this study apart from others is that instead of looking at the tumor as a whole, the researchers looked at individual tumor cells—over 24,000 to be exact. They looked at each cell’s genes; not the DNA, which is the same in every cell of the body, but the RNA, which shows which specific genes are being made into proteins and varies between different cells.
Despite all of the tumors being different, the researchers were able to classify all the cells into just four different states based on which genes they were expressing. All of these states resembled cells normally found in the brain, but with a cancerous spin. Some were like neural progenitor cells, which are able to form into neurons and other brain cells called glia. Others looked more like oligodendrocyte progenitor cells, which go on to become a type of glia that form the insulation around neurons. A third type looked like astrocytes, a different type of glial cell that performs many support functions in the brain. And the last type looked like mesenchymal cells, which are a variety of cell types involved with blood vessels, connective tissue, and the immune system (Figure 1).
Each tumor the researchers analyzed contained cells in at least two of the four states, and most tumors were composed of cells from all four states. However, the abundance of one cellular state or another varied from tumor to tumor, helping to explain why glioblastoma looks so different patient to patient. Additionally, although most tumor cells corresponded primarily to just one of these four states, about 15% of cells were clear hybrids of two. While cells of each of these four states were dividing and causing the tumor to grow, this division was especially prominent in cells that were neural or oligodendrocyte progenitor-like.
What might be causing cells to choose one of these four states? The scientists thought that certain genes or the environment around the tumor cells could be influencing whether they take one state or another. Using tissue samples from The Cancer Genome Atlas, they confirmed that specific genes were associated with each of the four cellular states: EGFR with astrocyte-like, PDGFRA with oligodendrocyte precursor-like, CDK4 with neural progenitor-like, and NF1 (along with environmental cues) with mesenchymal-like. To investigate how these genes might favor one cellular state or another, they grew healthy neural progenitor cells from mice in a dish and forced them to overexpress one of the identified genes. Normal cells forced to express too much EGFR produced astrocyte-like cells, while normal cells forced to overexpress CDK4 formed neural progenitor-like cells. The genes also caused the cells to divide more. These results suggest that these specific genes can push normal cells towards one of the four particular cancerous cellular states found in glioblastoma.
Now that scientists know that tumor cells can be only one of four cell states, it should be easier for doctors to treat glioblastoma by targeting the most abundant cell type in the tumor, right? Unfortunately, these cancer cells have another trick up their sleeves. It turns out that glioblastoma cells can switch between the four states. When scientists isolated cells in a particular state and then used them to initiate new tumors in a mouse model, they found that no matter what state they started out with, the new tumor always had cells in multiple cellular states, often in the same distribution as the original tumor! To be even more sure that the cells could switch states, researchers used viruses to give certain cancer cells unique barcodes before initiating a tumor. When they checked back later, not only did they find the same barcode in many cells (indicating that the cells divided and the tumor grew), but cells with the same barcode were in different states. It’s possible that because glioblastoma cells are able to switch states, treatments targeting one state (or gene associated with one state) might just cause the cells switch to another state that isn’t affected by the treatment. Hopefully with this new information, researchers will be able to develop therapies that target multiple cell states at once, wiping out this terrible disease once and for all.
- National Organization for Rare Disorders. Glioblastoma. 1–9 Available at: https://rarediseases.org/rare-diseases/glioblastoma-multiforme/.
- Wirsching, H.-G., Galanis, E. & Weller, M. Glioblastoma. in Handbook of Clinical Neurology (eds. Berger, M. S. & Weller, M.) 134, 381–397 (2016).
- Neftel, C. et al. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell 1–15 (2019). doi:10.1016/j.cell.2019.06.024
Cover Image by Hellerhoff via Wikimedia Commons, CC BY-SA 3.0. https://commons.wikimedia.org/wiki/File:Glioblastoma_multiforme_-_MRT_T1KM_cor.jpg
Figure 1 created with BioRender