Gliomas are tumors infiltrating the brain and CNS and make up 80% of malignant tumors of the brain. Especially with incurable glioblastoma multiform (GBM), there is a dire need to better understand their unique disease biology. Studies have shown that gliomas dramatically change their local microenvironment and that disease progression is associated with a variety of cognitive and behavioral symptoms, including epileptic seizures. This raises the question:
How do gliomas interact with our brain cells?
Neuronal roots of epileptic seizures
Epilepsy is a summary term for a group of neurological disorders characterized by seizures, impacting the lives of 70 million people worldwide. Seizures are provoked by abnormal electrical activity in the brain (Gosh S. et al., MDPI, 2021) and can have many causes, from viral meningitis to head injury to birth defects to tumors.
Epileptogenesis in brain tumor patients is multifactorial and glioma patients less frequently respond to anti-epileptic medication. Tumor location influences epileptic risk, intractable epilepsy is particularly frequent in tumors that involve the temporomesial and insular structures of the brain (Chang EF. et al., J Neurosurg., 2008).
Seizures, the most common neurological symptom, afflict >80% of low-grade glioma patients and 50%–60% of high-grade glioma patients and can contribute significantly to the deterioration of cognitive function (Rudà et al., Curr Opin Oncol., 2010)
There is increasing evidence that metabolic neurotransmitters play an important role in the development of seizures and also in the progression of glioma diseases (Lange F. et al., MDPI, 2021 , Gosh S. et al., MDPI, 2021), but does this also mean that there is a synaptic connection to gliomas?
Bridge to mayhem
Synapses usually form between neurons and normal oligodendroglial precursor cells, where electrochemical signaling can regulate proliferation, differentiation, or survival of those cells (Kougioumtzidou E. et al., Elife, 2017).
Interestingly, primary glioma cells express a repertoire of synaptic genes and can participate in neuron-glioma synapse formation. Furthermore, studies have shown that glioma can build electrochemically functional synapses that exhibit properties similar to normal oligodendroglial synapses (Venkatesh et al., Nature, 2019).
Furthermore, gap junctions couple adult glioma cells through tumor microtubes (Osswald M. et al., Nature, 2015) to neurons, causing some of the heterogenous glioma cells to amplify currents and form a ‘glioma network’.
Together, these observations strongly suggest that activity-regulated increases in extracellular potassium concentrations cause glioma depolarization and that a gap junction-coupled glioma network amplifies the consequences of activity-induced changes in the extracellular ionic environment.- Venkatesh et al., Nature, 2019
Electrical and synaptic integration of cancer cells into neural circuits promotes glioma progression (Venkatesh et al., Nature, 2019), but causes neuronal hyperexcitability and abnormal spiking, the hallmarks of seizures.
Cancer cells profiting from the local microenvironment is of course a larger feature of many tumors, and yet this network formation into functional microcircuits is remarkable.
It might even be a critical component of glioma invasion and subsequent resilience to treatment.
Feeding off of neuronal activity
Neurons are not only a critically important component of the glioma microenvironment, but their neuronal activity is manipulated to also regulate malignant growth in an activity-dependent manner.
In the brain, everything is connected to neuronal activity, synapse formation, cytoarchitecture, cell type differentiation, and even neurovascular coupling (check our recent blog article about the latter).
This has profound implications, as glioma-related disruption of neurovascular coupling within tumor-burdened regions of the cortex leads to hypoxia, which triggers hyperexcitability in neurons, as well as a general desynchronization of neuronal activity (Montgomery MK. et al., Cell reports, 2020). Hypoxia-induced growth factors have also been shown to stimulate glioma cell migration and invasion into the surrounding brain tissue (Monteiro et al., Cells, 2017). And just to make things worse, hypoxia can be caused by hypoxemia (low oxygen in the blood supply), already a risk during epileptic seizures (Rheims S. et al., Neurology, 2019).
Tumor-induced hypoxia causes seizures that in turn reduce the oxygen supply to provoke further tumor invasion and more seizures are a terrifying example of an amplifying feedback loop. A vicious cycle.
Our results thus suggest that episodes of seizure-induced hypoxia could feed into a vicious cycle of disease progression that includes glioma dispersion and expanding regions of neuronal dysfunction and vascular dysregulation with increasing frequency of seizures that cause progressively larger regions of tissue hypoxia. — Montgomery MK. et al., Cell reports, 2020
Vicious circles are of course only one example of how gliomas can thrive by subjugating their surrounding microenvironment, with many more complex interactions yet to be discovered.
This work demonstrates the complex ways in which glioma infiltration has widespread effects on brain synchrony, neuronal function, and neurovascular coupling, profoundly influencing many aspects of brain physiology and metabolism. Our results provide a dynamic picture of the way in which these functional alterations could shape disease progression, and relate to comorbidities such as seizures, exposing new targets for clinical therapies and interventions. (Montgomery MK. et al., Cell reports, 2020)
Today, researchers are frantically trying to understand and manipulate the interphase of integrated glioma-neuronal circuits because of their unique biology.
But that unique biology also gives some hope. Glioma metastases rarely manage to function outside of the neuronal environments, they might be dependent on their neuronal victims to persist.
Given that glioma infiltrates extensively within the brain and spinal cord and rarely metastasizes outside the CNS, neurons as a crucial component of the glioma milieu potentially confer important microenvironmental dependencies to the pathogenesis of the tumor (De Luca C. et al., Cells, 2022).
In biology, dependency is often another word for vulnerability
This means that if researchers were to sabotage that electrochemical link and break off these connections, tumor cells that depend on their neuronal victims might find themselves exposed to new interventions, for example, drug combination therapy (Gosh D. et al., Clin Transl Med., 2018).
That might not be a magic bullet to cure gliomas, but a multi-pronged approach has seen great benefits for patients suffering from a variety of cancers.
Glioma progression is uniquely intricate because of our brain’s diverse cell types, cytoarchitecture, neurovascular coupling, and overall complexity.
Cancer cells have been known to take advantage of their environment, from prostate cancers feeding of available androgen to renal cancers manipulating the vascularization. But for no cancer does this hijacking of available organ machinery and mechanisms seem more true, and more pernicious, than for gliomas.
The usurpation of available neuronal circuitry by an expanding cancer cell network is fascinating and terrifying at the same time.
Tissue invasion and connecting to neuronal circuits makes surgical resection much harder and comes with devastating clinical and psychological consequences to patients. Yet understanding that the hijacking of brain cells often comes with a reliance on their function might also constitute a new vulnerability that scientists can target in their fight against brain tumors.
Today, researchers are working tirelessly on new in vitro culture systems, including 3D co-culture and mixed brain/glioma organoids, that will allow them to open the door to drug discovery efforts and new neuroprotective compounds.
Even if a cure might be far-fetched, rescuing our neuronal hostages from their glioma hijackers might already come with treatment benefits to patients, maybe even giving hope that disease progression will no longer rob them of their body control, thoughts and personality.
And that is something to strive for.
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Declaration of interest:
The author is an employee at 3Brain.