Science Editor

A rare disorder, but, some say, not rare enough. That judgment fits the case of neurofibromatosis Type 2, a wide-spectrum cancer complex.

"The two main types of tumors they develop," explained molecular geneticist Andrea McClatchey at Massachusetts General Hospital, are called schwannomas and meningiomas. "These are relatively benign tumors of the central nervous system," she added. "And the hallmark they develop wraps around cranial nerves or the spinal nerve roots.

"The schwannomas and meningiomas develop a meninge tissue, which covers the brain and spinal column. These tumors develop in particularly intractable locations from a surgical point of view," McClatchey pointed out. "For a peculiar reason that no one understands yet, the first place they wrap around are the vestibular or auditory nerves. NF2 patients almost universally develop schwannomas on both of their auditory nerves. So often the first signs of disease are dizziness, ataxia and tinnitus along with the deafness.

"The age of onset for neurofibromatosis is usually in the teens and early 20s," McClatchey continued. "The epidemiological incidence, I am told, is between about 1 in 35,000 of the population and 1 in 40,000. So it's quite rare. NF2 is not a sporadic disease. Rather, it's one of the dominant inherited predispositions to develop tumors. Mortality rate is quite high. Although benign in nature, these tumors are quite difficult to remove, partly because of their inaccessible location They wind themselves around absolutely critical cranial and spinal nerves."

McClatchey is senior author of a paper in the journal Genes & Development from Cold Spring Harbor Laboratory Press dated May 1, 2003. Its title: "NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions."

"The most important finding of our paper," McClatchey told BioWorld Today, "is that we have for the first time identified one of the critical functions of the NF2 tumor suppressor. This is a tumor suppressor that we've known about for a decade, and there have been all kinds of speculation about how it works.

"We believe that this is one of the first findings of a clear and important identification of an NF2 tumor suppressor, which tells us how it works. NF is a relatively rare disorder, but of course that disorder led to the identification of this gene. So it's very important for the families of NF patients because they have been breathlessly waiting for the cloning of the gene to understand how the encoded protein works. I don't say we understand that by any stretch of the imagination now, but I think we have our hands on something that's clearly an important function for the tumor suppressor."

Families Of NF Patients Await New Gene Discovery

"So it's important for the NF2 patients' families. But moreover, we've learned two things over the past decade. One is the kind of cancer that NF2 patients are treated for is actually quite common - in a sporadic form in the normal population. So obviously this new information is also germane to the eventual treatment of those patients.

"But my studies," she went on, "have focused on developing a mouse model for neurofibromatosis. And everything that we have learned in the past six or seven years about the function of this gene in the mouse may be important in a far broader spectrum of cancers than we previously thought. When we began generating animal models," she recounted, "the mice we raised developed a broader spectrum of cancers. We found that the tumors developed in our mice metastasized relatively remarkably for a mouse. So we began to wonder whether or not loss of NF2 in other kinds of cancers would contribute to tumor metastasis. The knockout phenotype of the mice was just right. At that time, a few years ago, we wanted simply to generate a genetic analogue of the human NF2 patient. So we raised mice, which were heterozygous - one wild-type copy and one mutant copy of the NF2 genes. We aged those animals to see if they would eventually develop cancer, and it turned out they did. They didn't spontaneously produce the same kinds of tumors that our human cancers develop. Instead, they came out with a variety of tumors, particularly of the bone and liver. In both cases these were very highly metastatic. They were not typical of the human condition.

"In those early studies there was one form of human cancer, mesenthelioma, that showed up where the tumors were found to have mutations in both copies of the NF2 gene, which is typically associated with asbestos exposure. These kinds of tumors, schwannomas and meningiomas in humans, regardless of whether or not they are genetic mutations or sporadically occurring tumors, by nature rarely metastasize.

"Upon cloning the NF2 gene," McClatchey went on, "we immediately knew something about the nature of its encoded protein. That was named merlin' by Jim Gusella, who had discovered the Huntington's disease gene in 1993. NF2 patients," McClatchey pointed out, "inherit a heterozygous mutation. One copy is normal, the other mutated. They are all inactivating mutations - a complete loss of function, the function being tumor suppression. That was the big black box, where we think our paper has contributed an important piece of information."

NF2 Mice Offer Arsenal Of Tools, Reagents

"For us the development of the mice had a second equally important ongoing motivation behind it. And that was because we'd be able to generate cells derived from the mice. They represented an arsenal of tools and reagents," McClatchey said.

"So we could go in and ask a specific tumor suppressor what happens in a cell when we test the function of that single gene. And that's where we think this particular paper, and the identification of the adherens junctions and merlin as an important function, came about. I may mix and match my biotech vs. pharmaceutical ancestors," McClatchey observed, "the more we have ideas about developing therapeutic strategies. The notion of working to re-establish adherens junctions in a pharmaceutical manner as a potential therapeutic strategy is not a ridiculous idea. These are proteins," she concluded, "that fit in a different physical location in a cell which may have advantages and disadvantages for therapeutics."