A Killer Hidden in the Brain
Glioblastoma (GBM) doesn’t knock—it crashes in. It’s the most aggressive form of brain cancer known to modern medicine. Often, it’s discovered late, grows fast, and responds poorly to therapy. Despite the best surgical tools and targeted drugs, GBM continues to outmaneuver treatment. But why?
Recent studies show that glioblastoma’s power lies not just in how fast it grows, but in how it hijacks our body’s signaling systems—the same molecular messages responsible for normal cell survival, growth, and repair. Understanding these hijacked pathways could be the key to stopping this formidable disease. [1]
What Is Glioblastoma?
Glioblastoma is a malignant brain tumor that originates from glial cells—the supportive tissue in the brain. It falls under the category of gliomas, and it’s the most severe type (WHO Grade IV). The standard treatment includes surgery, radiation, and chemotherapy, but even with aggressive therapy, recurrence is common. Survival time often averages just over a year.
GBM isn’t a single disease. It has multiple subtypes, each with different mutations, gene expressions, and levels of severity. Among the most significant genes involved are:
- EGFR (epidermal growth factor receptor): Often mutated or overexpressed in GBM, leading to uncontrolled cell division.
- TP53: A tumor suppressor gene frequently altered in many cancers, including GBM.
- NF1 and PTEN: Genes that act as brakes in important signaling pathways; when these are disabled, the brakes are off—and cancer runs wild. [1]
The Pathways That Fuel GBM
To understand glioblastoma is to understand how it rewires the body’s normal growth signals.
- MAPK Pathway (Mitogen-Activated Protein Kinase): This pathway normally helps cells grow and respond to stress. In GBM, it’s often hyperactivated, fueling relentless cell division.
- PI3K Pathway (Phosphoinositide 3-Kinase): Like MAPK, this pathway is critical for survival and growth. In many GBM patients, the PI3K pathway is stuck in the “on” position, sometimes because of loss of PTEN, a gene that usually keeps it in check.
- cAMP Pathway: Normally involved in signaling within the cell, cyclic AMP is found at reduced levels in GBM. It also interacts with the MAPK and PI3K pathways, creating a web of dysregulation that supports tumor growth.
Together, these altered signals allow glioblastoma to grow, invade, and resist treatment. [1]
Why Can’t We Just Cut It Out?
That’s a common and fair question. In most cancers, removing the tumor—and a little extra tissue around it—is a good strategy. But in the brain, the stakes are different. Removing too much can damage critical functions like speech, memory, or movement. Even when surgery is aggressive, microscopic tumor cells often remain behind—and they’re often the toughest.
The Role of Cancer Stem Cells
One of GBM’s most terrifying strengths is its ability to bounce back after treatment. A key reason? Cancer stem cells (CSCs).
These cells possess a trait called stemness—the ability to replicate endlessly and produce many different cell types. CSCs in GBM:
- Survive therapy by activating stress responses
- Repopulate tumors even after remission
- Change form (a trait called plasticity) to resist drugs
- Migrate and seed new tumor regions
Because they aren’t a single type of cell, but a flexible population, these CSCs create tumor diversity that’s very hard to treat. Even if one therapy works on some cells, others survive and adapt. [2]
Artstract by J. Deitz
A Glimmer of Hope: Targeting Signaling and Stemness
While there’s no cure yet, scientists are exploring therapies that:
- Inhibit key signaling proteins in the MAPK and PI3K pathways
- Restore function to tumor suppressor genes like PTEN
- Target cancer stem cells to prevent tumor regrowth
Personalized medicine—tailoring therapy to an individual’s unique tumor profile—offers a promising future. Understanding the signaling chaos behind GBM is a big step in that direction. [3]
Conclusion: The War in the Brain
Glioblastoma is a master strategist. It hijacks signaling, outwits treatment, and hides behind the blood-brain barrier. But science is catching up. With deeper understanding of its pathways and the stubborn stem cells that fuel it, we may someday turn this killer into something we can fight—and win.
To find out more about glioblastoma click here.
[1] N. H. Fung et al., “Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer,” Cellular Signalling, vol. 57, pp. 2–9, May 2019, doi: 10.1016/j.cellsig.2019.01.011.
[2] P. M. Aponte and A. Caicedo, “Stemness in Cancer: Stem Cells, Cancer Stem Cells, and Their Microenvironment,” Stem Cells International, vol. 2017, pp. 1–17, 2017, doi: 10.1155/2017/5619472.
[3] J.-J. Loh and S. Ma, “Hallmarks of cancer stemness,” Cell Stem Cell, vol. 31, no. 5, pp. 617–639, May 2024, doi: 10.1016/j.stem.2024.04.004.
