As news of Senator Ted Kennedy’s diagnosis of malignant glioma traveled throughout the country and beyond, it was an opportunity for people to learn more about an otherwise rare form of cancer. Most adult brain cancers are caused by the spread of late-stage cancers from other parts of the body that deposit and grow as secondary tumors within the brain. However, gliomas are an entirely different beast. They originate in the brain from a specialized type of cell called a glial cell. When it comes to cells within the brain, neurons have grabbed the limelight for years. But in fact, glial cells outnumber the more famous neurons at a ratio of 10:1. Besides abundance, the importance of glial cells has surfaced over the last few decades.
It is now well appreciated that glial cells establish an optimal environment in which our neurons can operate safely. Normally glial cells maintain a proper balance of stimulatory signals in the brain, provide growth support to neurons, and alert the greater immune system if problems exist within the tightly controlled neural space. Unfortunately, dysregulation within these critical cells can have dramatic consequences, especially when they become cancerous and develop into devastating and difficult to treat gliomas.
What is a Glioma?
Like cancers in other parts of the body, gliomas are thought to originate from stem cells. In this case, gliomas arise from neural precursor cells that otherwise create neurons and glia. These stem cells may become cancerous when harmful mutations occur in genes that normally suppress tumor formation.
There are many different kinds of gliomas. However, all gliomas are subject to unique limitations given their location within the brain. One such constraint is the restricted space in which they can grow due to the bony confines of the skull. Early brain tumor growth models proposed that neighboring brain regions are compressed as a result of a tumor’s expansion. However, more recent evidence suggests that gliomas might actually play an active role in killing off healthy brain tissue in order to facilitate tumor growth.
Greedy Gliomas
Within the last decade, researchers have discovered that glial tumor cells are defective in the maintenance of the neurotransmitter glutamate. Normally, neurons release glutamate in a controlled fashion, after which it is quickly reabsorbed by adjacent neurons or glia. When glutamate uptake is impaired, neurons die as a result of what is termed “excitotoxicity”, which is essentially a prolonged state of over-stimulation that exhausts the neurons. Biopsy studies have found that brain tissue from glioma patients is defective in glutamate absorption. Furthermore, research laboratories have shown that gliomas inappropriately release glutamate. Thus, glial cells appear to undergo specific changes during their transformation into cancerous gliomas that contribute to the establishment of a glutamate-rich environment. This toxic buildup of glutamate kills surrounding neurons and clears brain space in which the glioma may then expand.
Excitotoxicity-mediated displacement of normal brain tissue by gliomas often results in seizures due to neuron over-stimulation. Other early warning signs of glioma include language impairment, personality changes (such as apathy), headaches, nausea, vomiting or cognitive difficulties. Because these symptoms are also associated with a range of other diagnoses including depression, migraine and stroke, the sudden onset of seizures may be the first inkling that the underlying cause is actually due to a glioma.
Current and Future Treatment Options
Gliomas are among the most aggressive cancers. If they are caught early, the patient may live up to 5 years. However, if diagnosed at a late-stage, survival is often only 6-12 months. This poor prognosis is due in part to largely ineffective treatments.
Typically, a patient with glioma will undergo brain surgery, followed by chemo or radiation therapies. Unfortunately, surgery is rarely able to remove all of the glioma, often because precaution is taken to avoid damage to vital brain regions adjacent to the tumor. In addition, the subsequent chemotherapy is less efficient than it could be for several reasons. First, a protective cellular barrier exists to restrict the travel of material in and out of the brain. This barrier prevents foreign and potentially harmful material circulating within the blood, including chemotherapeutic drugs, from entering the brain. Second, most chemotherapeutic drugs are indiscriminately toxic to all replicating cells. Usually, chemotherapy drugs are administered at the lowest dose that is still able to kill hyper-proliferative cancer cells, while maintaining minimal toxicity to healthy tissue. However, because of the protective brain barrier, considerably higher amounts of drugs would be required to deliver a lethal dose to the glioma residing within the brain. Unfortunately, doses high enough to definitively kill gliomas are not feasible for patients because of the adverse effects to other organs.
Development of drugs specific to the underlying biology of the glioma would considerably reduce the unintended toxicity associated with traditional chemotherapies. The role of glutamate imbalance in glioma progression makes it an ideal drug target. In fact, scientists are pursuing the development of drugs that can inhibit glutamate release by glial cells. Such inhibitors may slow the death of the surrounding normal brain tissue and even the expansion of the glioma itself. These effects could improve quality of life, as well as increase the life expectancy of glioma patients.
The Kennedy Legacy
In addition to his forty years in politics, Senator Kennedy is also known as a champion of healthcare. Now, through his recent health struggle, he has given a face to a relatively unfamiliar disease. Hopefully, the heightened awareness of glioma, as well as the need for a greater understanding of glia biology to aid in the development of more effective treatments, will continue to endure as a result of its association with the Kennedy legacy.
–Maria LC Powell, Harvard Medical School
For More Information:
More information from the New York Times:
< http://www.nytimes.com/2008/05/21/health/21tumor.html >
Brain Tumors, from the Dana Foundation:
< http://www.dana.org/news/brainhealth/detail.aspx?id=9792 >
Primary Literature:
Louis, DN. Molecular Pathology of Malignant Gliomas. Annu Rev Pathol Mech Dis. 1:97-117. (2006)
Sontheimer H. A role for glutamate in growth and invasion of primary brain tumors. J. Neurochemistry. 105:287-295. (2008)