The 7 horrocruxes of glioblastoma


Paraphrasing Socrates: “There is only one good, knowledge, and one evil, ignorance”. If scientists were to highlight a positive effect of the current pandemic situation, it would be the emerging interest of better understanding biomedical research. Cancer is one of the silent pandemics which humans have suffered from throughout the history, but it seems that its severity has been unfortunately hidden by the COVID pandemic.

No organ or tissue is spared from developing cancer. It might sound unbelievable, but brain cells can also become tumorogenic: glioblastoma is the most aggressive brain cancer. Specifically, the overall median survival is estimated to be around 14.6 months upon diagnosis, which means that only around 5% of people suffering from glioblastoma might survive more than 5 years.

In order to become familiar with the molecular basis of glioblastoma, and being also the 20th anniversary of Harry Potter, I would like to talk about horrocruxes. Harry Potter’s nemesis, Lord Voldemort, pretended to achieve immortality by hiding seven fragments of his soul in objects that are named horrocruxes. Likewise, mutations that accumulate in brain cells favor their transformation into tumoral cells of, which lay its hallmarks of immortality in seven fundamental characteristics. Let’s go through the 7 horrocruxes of glioblastoma that scientists might encounter!

Figure 1: The 7 horrocruxes of glioblastoma. Seven features of glioblastoma that explain how this cancer is so aggressive and why it is so difficult to treat.

The first horrocrux of glioblastoma is the mosaic of cells: the tumoral mass integrates cells with a variety of different genetic and molecular characteristics. These cells are very heterogeneous and differ one from another, which is the cause of one of the main pitfalls for treatment efficiency. This property is inherent to glioblastoma cancer stem cells, which could be regarded as the golden charmed objects that surrounded one of the horrocruxes found by Harry Potter: if accidentally taken, they would start to exponentially multiply. The same that occurred with this horrocrux can be observed in brain tumors when they are eliminated by surgery. Specifically, glioblastoma cancer stem cells resting at the niche of the brain can exponentially multiply, and thus they might end up repopulating the tumoral mass with new tumoral cells: the glioblastoma rises again. Consequently, glioblastoma is a relapsing and recurrent tumor that can reappear with certain frequency even if it has been already “defeated”. Some people might say that “second parts were never good” and, in this case, the second occurrence of glioblastoma is associated with a high resistance to radiotherapy and chemotherapy treatments.

Unlike other types of cancer, glioblastoma is protected by a natural shield due to its brain location: the blood-brain barrier (BB barrier). The BB barrier is a filter of molecules that selects those with access to the Central Nervous System. Only those molecules, which are small and lipophilic and hence have a higher affinity towards lipids than water, have the ability to cross the BB barrier. The BB barrier is very selective: it does not only filter nutrient molecules and waste products, but also biochemical drugs. It is estimated that up to 98% of all molecules, including glioblastoma diagnostic and therapeutic agents, are unable to enter the Central Nervous System or, at least, reach therapeutic concentrations. Therefore, there is an urgent need to develop new drugs that may allow more effective personalised treatments. New clinical approaches to glioblastoma are currently based on nanomedicine (i..e., from nanobodies and nanoparticles to viruses able to destroy tumoral cells) and immunotherapy (i.e., methods to visualise the presence of the tumoral mass in the immune system so it can be activated). These two areas are based on molecular whistleblowers that allow the development of novel diagnostics and treatments exclusively targeting the tumoral mass. They are exclusive molecules of glioblastoma cells that appear due to the molecular anarchy triggered by the tumor itself to keep protected its immortality. However, although they stimulate the tumoral growth and maintenance, this molecular whistleblowers are lighthouses that indicate the presence of the tumor and define its biological characteristics. Once the molecular whistleblower is identified, we can then develop novel targeted treatments against cancer. We could see them as the unwished horrocrux of glioblastoma.

In essence, the 7 horrocruxes of glioblastoma could be seen as the knowledge that the scientific community has gained through decades of research. If the 20 hours that spans the Harry Potter movies could collect more than 7,700$ millions, imagine what could be done in Research and Innovation in Spain if this funding was available to research in glioblastoma! If the only good is knowledge, then let’s seriously bet on it.

By Eduardo Ruiz López, @eduruiz_94. Postdoctoral researcher at Asociación Española contra el Cáncer at Instituto de Investigación Sanitaria Aragón (IIS Aragón), Spain.