by Hannah Farnsworth
figures with Xiaomeng Han
Most people know someone in their life who has been impacted by cancer, and a staggering 40% of us will be diagnosed with cancer in our lifetimes. Despite the prevalence of cancer in the general population, there are many types of cancer that still lack effective treatments. One such form of cancer is a type of brain tumor called high-grade glioma. Glioma tumors are caused by the abnormal growth of precursors for a type of brain cell called glial cells. Under normal conditions, glial cells support the growth and function of neurons, the brain cells that control our thoughts, movements, and emotions. In a cancer disease-state, unhealthy glial progenitors infiltrate and intertwine with normal brain tissue, forming glioma tumors and impacting neuronal function. Glioma tumors are labeled as high-grade when they grow at a fast rate and quickly impede the brain’s ability to control important functions that keep us alive. Of the ~90,000 Americans diagnosed with primary brain tumors every year, approximately 14% will receive a high-grade glioma diagnosis. Once detected, these patients have an average life expectancy of less than two years. Unfortunately, the characteristics that make these tumors so fast growing also make them exceedingly difficult to treat.
Why are some glioma tumors resistant to traditional therapies?
The mortality rate of high-grade gliomas is in part due to the interconnected, mesh-like network that these tumors form within the brain (Figure 1). Individual glioma cells are connected to each other by cellular extensions that allow the tumor to share nutritional and growth-promoting factors over long distances. This communal network also causes tumor resistance to traditional cancer therapies. The two most common cancer treatments, chemo and radiation therapies, work by attacking fast-growing cancer cells, and are largely ineffective at preventing the growth of high-grade gliomas. The brain is innately protected from circulating chemicals in the bloodstream, so it is difficult for these treatments to effectively reach and penetrate the tumor. Doses that reach the tumor are minimally effective, because healthy cells in the network are able to support areas damaged by the treatment and continue helping the tumor grow.
Properties of the tumor network lower the effectiveness of traditional therapies, so surgical removal of the tumor is a common course of treatment for high-grade gliomas. The expansive growth pattern of these cellular networks, however, makes it exceedingly difficult to remove the entire tumor. Brain tissue infiltrated by glioma cells remains functional, so it is often necessary to leave portions of the tumor behind after surgery to preserve cognitive function. For some other cancers where traditional therapies and surgery are ineffective, scientists have been able to identify factors that the tumor depends on for survival and make drugs that prevent the tumor from accessing these factors. For example, some breast cancers depend on the presence of estrogen to grow, and estrogen-blocking medications have made these previously deadly cancers curable. The un-targetable nature of glioma cells has led scientists to search for similar targets in the brain that may be supporting the growth of glioma tumors.
Glioma tumors hijack the brain to support their own growth
Cancer cells functionally adapt to use available resources in the surrounding environment to support their continued growth. After glial cells, neurons are the second most abundant cell type in the brain. This availability, combined with the neural-like genetic signature of glioma cells, made scientists wonder if glioma cells are somehow able to use neurons, or chemicals produced by neurons, to grow in the brain.
Neurons communicate by releasing chemicals called neurotransmitters across a connecting structure known as a synapse. Glutamate, an excitatory neurotransmitter, tells recipient neurons to increase their level of signaling with each other. In a ground-breaking discovery, the scientist team revealed that glioma cells form functional synapses with neurons and that these cancer cells respond to glutamate in the same way neurons do. This response to glutamate within the tumor enables glioma cells to grow and invade more brain areas. The scientists also discovered that glioma cells release factors that cause neurons to increase their signaling to each other, release more glutamate, and form more synapses with glioma cells (Figure 2). The combined effect of these neuronal changes is that glioma cells receive more growth-promoting factors from neurons. Since this original discovery, researchers have also identified similar growth-promoting properties of another neurotransmitter, GABA, suggesting that glioma cells are capable of interacting with many types of neurons and neurotransmitters. Collectively, these discoveries demonstrate that high-grade glioma tumors hijack the brain’s normal neuronal activity to support their own growth.
How can we use neurons to treat brain cancer?
By discovering that glioma tumors rely on neuronal activity to infiltrate the brain, a new target was identified for previously un-treatable glioma tumors. Drugs that block the tumor’s access to growth-promoting neurotransmitters may slow tumor progression and expand patient lifespan. The most direct method to prevent glioma tumors from accessing neurotransmitters is to prevent their release. Many drugs that do this already exist for treating psychiatric diseases like depression, anxiety, and bipolar disorder, as well as for epilepsy management. These psychiatric drugs employ diverse mechanisms that can target one or many different types of neurotransmitters. Using these medications for glioma therapy will require finding a medication that best blocks the neurotransmitters glioma tumors rely on to grow. As new research suggests they may use more than one type of neurotransmitter, a recent study decided to test the anti-epileptic drug levetiracetam that dampens universal neurotransmitter release. This study found that levetiracetam slows glioma proliferation and extends lifespan in mouse models. This study also performed a retrospective analysis on human patients and found this drug may be applicable in the clinic for slowing tumor growth.
A combination of therapies hold promise for glioma patients
Drugs like levetiracetam will most likely not be enough to cure high-grade glioma alone. These medications do not completely halt neurotransmitter release, as such blockage would lead to brain malfunction and patient death. Additionally, neurotransmitters are not the only factors glioma cells rely on for survival. Thus, while limited in their effects, neuronal medications can successfully lower a key source of growth-promoting factors, which may decrease the cancer’s ability to expand its interconnected network. This slowing would allow the tumor to become more vulnerable to traditional cancer therapies. A collection of clinical trials recently began that explore the benefit of adding different neurological medications to traditional glioma treatment regimens (Figure 3). Even if neuronal therapies can only help a small number of patients, they offer promise to those with no other alternatives. As scientific research advances and works to identify neuronal populations and transmitters most often hijacked by glioma tumors, therapies can become more targeted to help more patients. Hopefully targeted-neuronal therapies combined with traditional cancer treatments may one day make high-grade gliomas a curable form of brain cancer.
Hannah Farnsworth is a second year Ph.D. student in Harvard’s Program for Neuroscience where she studies how glioma tumors modulate brain circuitry.
Xiaomeng Han is a graduate student in the Harvard Ph.D. Program in Neuroscience. She uses correlated light and electron microscopy to study neuronal connectivity.
For More Information:
- To read more on cancer prevalence in the United States see the National Cancer Institute’s statistics report.
- To learn more about glioma tumor networks and therapy resistance read this 2015 Nature article.
- To read more on the functionality of glioma infiltrated brain tissue see this 2021 PNAS article.
- Read this 2019 Nature article to learn more about the discovery of functional neuron to glioma glutamatergic synapses and this 2022 BioRxiv pre-print from the Monje Lab at Stanford for the discovery of neuron to glioma GABAergic synapses.
- To learn more about combinatorial glioma therapies see this 2022 Nature Cell Biology Review.