The Brain's "Other Cells" Go Awry

Spring 1995 Volume 4, Number 2

BY DAVID N. LOUIS, M.D.

hen most people picture the cells that populate the brain, they envision neurons, those intelligent, busy cells that enable us to think, move and sense. Similarly, one's conception of neurological diseases is often formed by diseases of neurons, such as Alzheimer's disease or Lou Gehrig's disease.

The brain's "other cells" can become an unruly crowd, turing against the neurons they are supposed to serve. (Art from the Bettman Archive: Portait of the Artist Surronded by Masks; Ensor, 1899.)

But, while the glamorous neuron often grabs the spotlight, neurons are neither the most common, nor necessarily the most important, cells in the nervous system. A host of "other cells" populate and surround the brain and nerves, providing an essential entourage for the royal neuron as it goes about its important business.

Glial cells, for instance, outnumber neurons by about 10 to 1 in the human brain. These cells were originally thought only to provide a scaffold for neurons (the term "glia" means "glue cells"), but glia have a wide variety of integral functions, from participating in the conduction of neuronal impulses to responding to injury.

Schwann cells inhabit the nerves that issue forth from the brain, facilitating the nerve's ability to carry signals to the rest of the body. Meningeal cells ensheath the brain and spinal cord, protecting the nervous system and regulating its surrounds. Still other cells, such as cells of the immune system, also reside in the brain and subserve vital functions.

Brain tumors: the unruly crowd

The most common disease process to affect these "other cells" is neoplasia, or tumor formation, resulting in tumors of glia (gliomas, see picture at right), meningeal cells (meningiomas), Schwann cells (schwannomas) and immune system cells (lymphomas).

Malignant glial cells (identifiable by their orange-brown cytoplasm) surround some innocent neurons. (Photo courtesy of Dr. Louis.)

These tumors, particularly the gliomas and meningiomas, form the majority of those traditionally lumped together under the rubric, "brain tumor." Approximately 17,000 new brain tumors are diagnosed in the United States each year, with gliomas accounting for about 13,000 of those cases. In children, brain tumors are the second most common form of cancer, surpassed only by leukemias.

Unfortunately, many brain tumors are currently incurable. The majority of adult gliomas, for instance, are resistant to therapy and often cause death within a few years. Brain lymphomas, while far less common, have also defied therapeutic attempts.

Meningiomas and schwannomas, on the other hand, are generally benign and can be treated by surgical resection. However, the removal of benign tumors from deep regions of the brain may carry considerable risk to the patient, and therefore some meningiomas or schwannomas may not be curable.

Most brain tumors occur in otherwise normal adults; that is, in people without a family history of brain tumors and without a history of exposure to an environmental toxin.

Some unfortunate people, however, are predisposed, either because of an inherited or an acquired condition, to develop brain tumors. The inherited brain tumor syndromes, with cumbersome names such as neurofibromatosis and tuberous sclerosis, predispose patients to various combinations of gliomas, meningiomas and Schwann cell tumors. One of these syndromes, neurofibromatosis 1, was popularized by The Elephant Man (the story of a man who, as it turns out, did not have neurofibromatosis!).

On the other hand, acquired or non-hereditary syndromes may also predispose patients to brain tumors. Brain lymphomas, for instance, typically occur in patients with deficiencies of the immune system and are thus common in patients with AIDS, but can affect non-immunocompromised adults as well. While such inherited and acquired brain tumor syndromes are generally uncommon, they have been crucial to our developing understanding of brain tumor formation.

Bad genes foment trouble
Cancer is a genetic disease; that is, it arises from defects in certain genes, the genes that normally regulate cell growth and cell death. Some genes, known as oncogenes, promote normal cell growth. Other genes, known as tumor suppressor genes, have the opposite effect, to retard cell growth. The normal division of our cells, such as those that turn over in the skin or gastrointestinal tract, is a delicate balance of positive and negative growth signals from these genes (see illustration). Normal cell division illustration

Normal cell division (top panel) is a delicate balance (indicated by "+" and "-") of growth-promoting (oncogene) and growth-inhibiting (tumor suppressor gene) signals. Tumors may form when this balance is upset (bottom panel). (Drawing by Dr. Louis.)

This balance may be upset by either the abnormal overactivation of oncogenes or the abnormal inactivation of tumor suppressor genes. Most common human cancers are thought to arise from the combined alteration of several oncogenes and several tumor suppressor genes, although the combination, sequence and types of alterations appear to differ from one human tumor to another.

We do not yet understand why these genetic events occur - some are caused by environmental toxins, others may be random internal changes - but, for most human tumors, they probably occur gradually during our lives. Because multiple genetic changes must occur for a tumor to form, most cancers thus develop in older people.

On the other hand, those people who have a family history of tumors inherit a defective growth-regulatory gene, often a tumor suppressor gene. These people therefore harbor a defective gene in every cell in their body and so develop multiple tumors at relatively young ages. Whether cancer is inherited or acquired, however, the culprits are the same: bad genes.

The glioma story
Delineating the genetic basis of brain tumors has been the emphasis of a number of laboratories in the United States and abroad, including our laboratory at the Massachusetts General Hospital. Gliomas have offered an opportunity to look at how tumors progress from one degree of malignancy to another, since the common gliomas that affect adults have been divided into three grades, or estimates of malignancy: low-grade, medium-grade and high-grade (glioblastoma multiforme).

Some gliomas, often those that arise in younger adults, may begin as low-grade tumors and change over a few years into the higher-grade tumors. Other gliomas, typically those that occur in older adults, begin as high-grade tumors, without a clinical history of a prior, lower-grade lesion.

To date, the formation of low-grade adult gliomas appears to involve at least three genetic events, one being inactivation of the p53 tumor suppressor gene. The types of p53 alterations in brain tumors are different from those that occur in smoking-related or sunlight-induced tumors. Ominously, the evidence in gliomas points to random events in our bodies, rather than to distinct environmental factors. Such genetic observations agree with most epidemiological studies of brain tumors, which have not clearly implicated any common glioma carcinogens (including, it should be noted, cellular telephones and electric power lines).

Malignant progression from low-grade to medium- and high-grade glioma involves other tumor suppressor genes and oncogenes. Some of these genetic culprits have been identified, while others remain at large. Interestingly, many of these genes appear to guard a particular checkpoint in cell division, suggesting that the transition to higher-grade glioma is mediated by the release of a distinct cellular brake. Again, the genetic observations are supported by clinical estimates of prognosis, since patients with low-grade tumors may survive for five to ten years, while patients with medium- and high-grade tumors often die within two years.

Just as there appear to be clinical subsets of gliomas, there are genetic subsets. For instance, those glioblastomas with alterations of the p53 gene do not show activation of the epidermal growth factor receptor (EGFR) oncogene. Those tumors with p53 changes are probably the low-grade tumors which progress in younger adults, while those with EGFR changes are usually the high-grade tumors that present de novo in older adults.

Many pediatric brain tumors are also glial in nature but these, in contrast to the adult gliomas, are often benign and, in turn, have different genetic underpinnings.

Thus genetic studies are providing, perhaps for the first time, biological explanations for some very old and accepted clinical observations.

Other upstarts, other woes
Any of the brain's cells may undergo neoplasia if it undergoes the "wrong" combination of oncogene and tumor suppressor gene changes at the "wrong" time. Hence, meningiomas, schwannomas and other brain tumors.

Even neurons, if they suffer genetic mutations at susceptible times, may become neoplastic. Neuronal tumors, however, are quite rare because neurons do not divide after fetal life and tumorigenic genetic alterations can only be propagated in dividing cells. This apparent strength, which protects neurons from neoplasia, is at the same time their Achilles' heel, since the neuron's inability to regenerate underlies its hopeless susceptibility to degenerative conditions like Alzheimer's and Lou Gehrig's diseases.

Containing the uprising
The clarification of the genetic events that underlie brain tumor formation is only a first step. We have begun to identify and characterize the rabble-rousers, but we are still very far from understanding why they become troublemakers and how they effect such destruction. More importantly, we are far from controlling or preventing such uprisings in the future.

The next step, therefore, is to characterize all of the genetic events and to understand their biological sequelae. Once we understand these ramifications, we can begin to develop more effective strategies to deal with this unruly crowd.*

Dr. Louis is Assistant Professor of Pathology at Harvard Medical School and Massachusetts General Hospital.

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