By using flies, scientists at The Johns Hopkins University have linkedmutations in specific genes to about 200 tiny cells whose unchecked growthleads to fatal brain tumors. The success of their experiments, they say, isproving the insect's value as a model for cancer research.
Biology professor Allen Shearn has used flies for years to study how thefunctions of specific genes integrate with a variety of developmentalprocesses. But these recent findings proved particularly noteworthy asresearchers in his lab have started mapping pathways that stimulatecancerous growth, beginning in genetic material and culminating in deadlytumors.
Perhaps even more noteworthy, he says, is that one of the genes in the mostrecent fly experiments corresponds to a human gene that has been implicatedin the spread of cancer. In the past, most cancer research has beenconducted in mammals.
"It turns out that some people have known that there are mutations in fliesthat cause specific tumors, but they really hadn't been studied much,"Shearn says. "In humans, it's difficult because people get tumors, whichhave certain properties, but you really don't know if they're from the sameor different causes.
"In flies, however, we can know what the causes are, more or less. We knowthe mutations and we know they cause tumors in the brain. In the case ofthe three genes we examined, the tumors invaded the same host tissues withthe same frequency and the tumors grew at the same speed. Essentially, wefound that three different genes were using the same pathway. It wasremarkable."
One property in particular makes the fly an excellent source for the studyof cancer, Shearn says: The metastatic process is extremely fast. InShearn's lab, researchers discovered that they could transplant tumorousbrain tissue into the abdomen of a female fly and recover huge brain tumorswithin two weeks.
Careful analysis showed that the transplanted abdomen tumor gave rise to asmall number of abnormal cells in the host fly's brain that began tomultiply ferociously. "We could see how about 200 tumor cells grew to50,000, filling almost a third of the head, in less than two weeks," Shearnsays. "It's incredible how aggressive the cells are. This was really thefirst time I had a feeling for what cancer is all about. When you actuallysee how they spread and replace normal tissue, it's almost scary. They'revicious."
The fruit fly has often been used in the past to study mutations anddecipher general principles of genetic inheritance. But in recent years, those developmentalbiologists who call themselves "fly people" are increasingly finding thatthe genetics of the tiny fruit fly has a stunning parallel with humangenetics, 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 ascientist studying cancers in humans at the National Institutes of Healthwent 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 genewas," Shearn said. "Of course, today we know of many genes that areconserved in mammals and flies. What's also interesting, however, is thatthe signaling pathways are also conserved. And that's significant. Mostpeople think that's where the problem with cancer really exists -- cellseither misinterpret signals or they get the wrong signal. So the cells dothe best they can with the information they have. They're told to dosomething and they do it, and of course, that can lead to these terribleconsequences."
In the case of his recent NIH-funded experiments, the results of which werepublished in the journal "Development, Genes and Evolution," Shearnsuspects that one specific pathway was involved, and that the signalingmechanism from the genes to the small assortment of cells stimulated theextraordinary proliferation of cells.
"We think at least one of the defects in the system is caused by a genecalled TGF Beta -- Transforming Growth Factor Beta -- and the signalsthrough 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 -- inthe 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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