Jan. 8, 1999 By using flies, scientists at The Johns Hopkins University have linked mutations in specific genes to about 200 tiny cells whose unchecked growth leads to fatal brain tumors. The success of their experiments, they say, is proving the insect's value as a model for cancer research.
Biology professor Allen Shearn has used flies for years to study how the functions of specific genes integrate with a variety of developmental processes. But these recent findings proved particularly noteworthy as researchers in his lab have started mapping pathways that stimulate cancerous growth, beginning in genetic material and culminating in deadly tumors.
Perhaps even more noteworthy, he says, is that one of the genes in the most recent fly experiments corresponds to a human gene that has been implicated in the spread of cancer. In the past, most cancer research has been conducted in mammals.
"It turns out that some people have known that there are mutations in flies that cause specific tumors, but they really hadn't been studied much," Shearn says. "In humans, it's difficult because people get tumors, which have certain properties, but you really don't know if they're from the same or different causes.
"In flies, however, we can know what the causes are, more or less. We know the mutations and we know they cause tumors in the brain. In the case of the three genes we examined, the tumors invaded the same host tissues with the same frequency and the tumors grew at the same speed. Essentially, we found that three different genes were using the same pathway. It was remarkable."
One property in particular makes the fly an excellent source for the study of cancer, Shearn says: The metastatic process is extremely fast. In Shearn's lab, researchers discovered that they could transplant tumorous brain tissue into the abdomen of a female fly and recover huge brain tumors within two weeks.
Careful analysis showed that the transplanted abdomen tumor gave rise to a small number of abnormal cells in the host fly's brain that began to multiply ferociously. "We could see how about 200 tumor cells grew to 50,000, filling almost a third of the head, in less than two weeks," Shearn says. "It's incredible how aggressive the cells are. This was really the first time I had a feeling for what cancer is all about. When you actually see how they spread and replace normal tissue, it's almost scary. They're vicious."
The fruit fly has often been used in the past to study mutations and decipher general principles of genetic inheritance. But in recent years, those developmental biologists who call themselves "fly people" are increasingly finding that the genetics of the tiny fruit fly has a stunning parallel with human genetics, and some papers based on fly research are actually now being accepted in publications such as "The American Journal of Human Genetics."
In fact, Shearn began his research on fly tumors 10 years ago when a scientist studying cancers in humans at the National Institutes of Health went searching for anyone besides herself who had located the NM-23 gene. Shearn had -- in flies.
"At the time, it was remarkable to discover how highly conserved the gene was," Shearn said. "Of course, today we know of many genes that are conserved in mammals and flies. What's also interesting, however, is that the signaling pathways are also conserved. And that's significant. Most people think that's where the problem with cancer really exists -- cells either misinterpret signals or they get the wrong signal. So the cells do the best they can with the information they have. They're told to do something and they do it, and of course, that can lead to these terrible consequences."
In the case of his recent NIH-funded experiments, the results of which were published in the journal "Development, Genes and Evolution," Shearn suspects that one specific pathway was involved, and that the signaling mechanism from the genes to the small assortment of cells stimulated the extraordinary proliferation of cells.
"We think at least one of the defects in the system is caused by a gene called TGF Beta -- Transforming Growth Factor Beta -- and the signals through the pathway are screwed up. We don't know exactly how yet, but ..."
One of his researchers is working on that right now -- using flies -- in the lab.
http://www.bio.jhu.edu/faculty/Shearn/Shearn.html -- Allen Shearn homepage
http://sdb.bio.purdue.edu/fly/aimain/1aahome.htm -- Fly Genetics
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