By David N. Leff

Q. Where does an invasive glioma go in the brain?

A. Wherever it wants to.

Neurobiologist Susan Hockfield puts it this way: "Malignant glioma cells travel relatively rapidly to great distances from their primary focus in the brain. It's so devastating," she pointed out, "because these tumor cells spread all over the brain. They're a moving target; you can't find them."

She explained that "in the mature brain, neurons never divide. Glial cells do, so they are really the trouble-makers, as far as cancer is concerned. A cell that can't divide won't become a tumor cell. A head injury can stimulate glial cells to start dividing in adults."

Hockfield is a professor of neurobiology at Yale University, in New Haven, Conn. Her laboratory there focusses on brain development. Gliomas occur when that development suddenly starts up again, years after glial cells have completed their prenatal program.

"One gene responsible for this process," Hockfield told BioWorld Today, "is re-expressed in these tumors, so you might characterize it as an oncofetal antigen. It looks very much," she added, "like re-expression of juvenile characteristics."

She described an experiment with rats at Dartmouth Medical Center, in Lebanon, N.H. "Investigators there," she recounted, "gave pregnant rat mothers a carcinogen. Their offspring, with some frequency, developed glioma brain tumors."

Glial cells come in several pursuasions, one of which — the oligodendral glia — is the sole manufacturer of myelin in the central nervous system. Except for causing brain tumors, their other functions are still subjects of intensive research.

Deadly Statistics Of Cancer Survival

Gliomas strike an estimated 15,000 to 20,000 victims a year in the U.S. alone, though one authority put the number at 28,000 in 1996. It is the leading killer of children with cancer. (See BioWorld Today, Jan. 23, 1997, p. 1.)

Because the tumors are so invasive, surgery, radiation and chemotherapy can rarely find and extirpate every last malignant cell. Median survival after such treatment is one year, with only 25 percent alive after two years.

"If you look at the survival statistics for glioma last year," Hockfield pointed out, "they are virtually unchanged from the survival curves for 1940. So there's a desparate need to do something for these people, but we don't know what an effective therapy is."

She and her colleagues have picked up that gauntlet, with a vengeance.

Hockfield is senior author of a paper in the semi-monthly Journal of Neuroscience, dated April 1, 1998. Its title: "Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion in vivo."

She discovered that seminal brain-enriched, hyaluronan-binding (BEHAB) protein in 1994, simultaneously with a separate group.

Her team found BEHAB molecules wherever they looked in glioma tumor cells, but nowhere else in the human or rat body. "We don't know BEHAB's normal function yet," Hockfield observed, "but we suspect it's important for cell migration. During fetal development," she continued, "we see it at very high levels, when glial cells are first being born. Once born, they have to move to where they're going, to do their business as adults.

"Our study," Hockfield went on, "shows that the full-length BEHAB molecule doesn't do any nasty stuff at all on its own."

Rather, she and her co-authors have apprehended a cleaved fragment of the sequence as the tumorigenic culprit. They named this N-terminal portion 'hyaluronan-binding domain' — HABD.

Hyaluronan, formerly known as hyaluronic acid, is a sugar found ubiquitously in the extracellular matrices of all cells. This is the narrow space between the cells' outer membrane and adjacent cells. "Over the years," Hockfield remarked, "many people have ascribed to the molecules in that space an important role in cell motility."

Gliomas Invade; Metastases Don't

She continued: "If you think about a breast cancer or a lung cancer that has metastasized to the brain, and a glioma growing in the brain, both of them make a lot of hyaluronan, yet one invades; the other doesn't." Finding out why is part of her agenda.

In hot pursuit of better treatments for glioma tumors, Hockfield has three main therapeutic targets in the cross-hairs of her ongoing drug-discovery project:

* "We could block the function of BEHAB itself. Pin down what it is about this molecule that makes glial cells invade. So we're trying to figure out the smallest possible piece of BEHAB that will confer this invasive property, and then target small compounds that could be delivered systemically to try to block it.

* "Another target is the protease that triggers the HABD cleavage. Once we understand more about this enzyme, how it works, we will again look for small compounds to attempt to block it.

* "Our third target is particularly interesting. We know that when glioma cells grow in a tissue culture dish, they don't make BEHAB. So there's some factor in the brain that induces glioma cells to express this protein. I have no idea what that factor is, but we're hoping to have some idea in the not-too-far-distant future."

She added: "This is all science fiction at this point. We're hoping to get there, but it's a long way off. I think," Hockfield concluded, "the exciting thing is that we've really unveiled a couple of new potential targets for glioma therapy, which were just not there a year and a half ago." *

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