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What’s All the Buzz? Fruit Flies Provide Unique Model for Cancer Research

David Tenenbaum

For almost a century, the fruit fly Drosophila melanogaster has been a workhorse of genetics and developmental biology: Genetically diverse, it is prolific, easy, and cheap to culture. Research with fruit flies dates to 1909, when Thomas Hunt Morgan of Columbia University started using them as a cheap, simple basis for experiments on genetics and development. This classic research subject has been used in several recent studies that have helped define the role of various genes in cancer.



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The fruit fly Drosophila melanogaster has been a workhorse of genetics and developmental biology for almost a century. This classic research subject has been used in several recent studies that have helped define the role of various genes in cancer. (©Lizzie Harper/Photo Researchers, Inc.)

 
Gerald Rubin, Ph.D., vice president for biomedical research at Howard Hughes Medical Institute and a veteran Drosophila researcher, said that cancer researchers have been using Drosophila "for a long time." In 1978, he pointed out, Elisabeth Gateff, Ph.D., (of Johannes Gutenberg University, Mainz, Germany) reported "striking similarities" between Drosophila and vertebrate neoplasms.

Researchers are still finding similarities. For example, in the Sept. 30 issue of the Proceedings of the National Academy of Sciences, Elizabeth Woodhouse, Ph.D., Lance Liotta, M.D., Ph.D., and colleagues in the Laboratory of Pathology at the National Cancer Institute’s Center for Cancer Research, identified a Drosophila gene called semaphorin 5c that is required for tumorigenicity.

In another report in October in Science, a team of researchers from Yale University reported on the genetic control of metastasis in fruit flies. Tian Xu, Ph.D., and colleagues studied mutant flies with non-metastatic eye tumors caused by an overactive ras gene. (Ras, the first human proto-oncogene to be discovered, is estimated to play a role in 30% to 50% of human cancers.) The researchers mutated a wide array of genes and found that scrib, which does not initiate tumorigenesis, does cause metastasis in tumors—if the tumor was initiated by ras. (Mutation, here, means a genetic alteration that increases, decreases, or halts gene expression.) Xu described scrib as a "cell polarity" gene, whose normal role in development is, almost literally, to tell the cell which way is up.

Xu found that tumors with ras and scrib mutations show "a whole range of characteristics of metastasis like human cancer," including degradation of the basement membrane (which encapsulates tissues and organs), induction of cell migration, reduction in levels of the adhesion molecule E-cadherin, invasion of nearby tissues, and finally the formation of distant, secondary tumors. "For a tumor to spread, it has to break through the basement membrane," said Xu. "We see exactly that in the fly tumor."

Tumors based on ras and scrib mutations were highly invasive, unlike tumors with mutations of scrib and a different oncogene. The fact that "ras can contribute to metastasis is new," said Xu. "To realize that the gene that started the tumor is also relevant to starting the metastasis is very important" to prognosis, he added.

What Advantages?

The utility of fruit flies as a cancer model rests in genetic and molecular similarities between flies and humans, Rubin said. "Most signal transduction pathways, molecular mechanisms involved in the control of growth, the cell cycle, are ancient, and conserved. Drosophila have all the pathways ... all the basic machinery involved in cell-to-cell communication and growth control. To the extent that there is knowledge to be gained from understanding these basic pathways, Drosophila is a great place to do that."

Price and convenience are also key. For example, "saturation genetics"—the search for every mutation that could cause a particular phenotype—requires the study of huge numbers of animals. "In fruit flies, that can be done by an individual [graduate] student in a year, at a cost of $20,000," Rubin said. "In mice, it would take 100 people and $10 million, but it’s never been done in a mouse. To do saturation genetics is just too expensive." Although saturation genetics might be feasible in yeast or the worm Caenorhabditis elegans, he added, "Flies are the most human-like of these model organisms for cancer research."

The genes of flies also tend to lack redundancy, said Amy Tang, Ph.D., in the Department of Biochemistry and Molecular Biology at the Mayo College of Medicine in Rochester, Minn., who traces signal cascades triggered by ras mutations in Drosophila. "In humans, you are always looking at a very dense forest, where everything is intertwined, and multiple genes are doing multiple things. When you knock out one gene, other genes may cover for its function. In fly work, and in other model organisms ... it’s much simplified." Using flies, she added, "You can understand the fundamental logic of tumor development, then apply it back to humans, because the mechanism is likely to be conserved."

Drosophila can also be used to unravel the chronological sequence of disease. Metastasized human tumors tend to have numerous mutations, masking the identity of those crucial to tumorigenesis and metastasis, said Tang. "Drosophila genetics is a very powerful approach to dissecting cancer biology, because with cancer, you are looking at the end point instead of the triggering event. With flies, we can go back and ask, what is the initial event that triggers the cancer?"

Flies can also be manipulated genetically in ways that would kill other organisms, Xu added. "If you mutate an important gene in every cell in an embryo, you will end up with a dead embryo, and then you can’t study how cancer would develop." But a trick called the genetic mosaic, which is especially easy with Drosophila, mutates only a few body cells. "Then you can ask what happens to these cells to ... show what are the tumor suppressors, and what the oncogenes do."

Finally, fly-cancer researchers can build on a mountain of data about flies, even work that focused on other topics. "It’s very hard to draw a sharp line between what is relevant to cancer and what is not relevant," Rubin said. "We did our work on ras signal transduction and tyrosine kinase, which are clearly relevant to cancer, but we did it because of their effect on cell fate determination [how cells differentiate and live or die during development]. We would not have called it cancer research," but information on signal transduction "has been shown to be important in human cancer."

What’s It Worth?

One illustration of the growing relevance of Drosophila in cancer emerges from the obscure hereditary disease, tuberous sclerosis (TS), which is associated with tumors in the brain, lung, kidney, skin, and other organs. Although human geneticists traced the disease to mutations in two genes, tuberous sclerosis complex 1 and 2, Xu said that "for many years, people didn’t know what these two genes [did], and there was no treatment."

Studies in fruit flies showed that the genes regulate growth and tissue size. Further fly work unraveled the signaling pathway and showed that reducing the activity of a downstream gene called S6kinase would block the defects associated with the TS genes. David Kwiatkowski, M.D., Ph.D., at Brigham and Women’s Hospital and Harvard Medical School in Boston, and others have now found the same pathway in mice, rats, and humans, and shown that S6kinase is indeed overactive in tumors patients with TS. Because the immunosuppressant rapamycin was known to inhibit part of the S6kinase pathway, the U.S. Food and Drug Administration has approved clinical trials for rapamycin in TS and a related disease, lymphangiomyomatosis. The trials will be performed by the Tuberous Sclerosis Program at Cincinnati Children’s Hospital Medical Center, and in England and Germany.

More evidence of the value of Drosophila research grows from the hedgehog pathway, said Matthew Scott, Ph.D., a developmental biologist at Stanford University. Hedgehog, a development-regulating gene, was identified during studies of normal development of fly larvae more than 20 years ago. In the developing organ systems in many animals, the activity of the secreted hedgehog signal is counterbalanced by a cell-surface receptor called patched; hedgehog stimulates cell division and patched restrains it. Scott said a mutation in patched, whether hereditary or caused by solar radiation, appears in most if not all basal cell carcinomas, the most common human cancer, and in medulloblastoma, a deadly childhood brain cancer.

The fly-based understanding of hedgehog and patched is nearing the clinic. HHMI investigator Philip Beachy, Ph.D., reported in Science in August 2002 that cyclopamine, a plant-based teratogen, killed cultured mouse and human medulloblastoma cells. And in Nature in September, Sarah Thayer, M.D., of Massachusetts General Hospital, Boston, showed that cyclopamine arrests the growth of human pancreatic cancer cells by blocking the hedgehog pathway. Tellingly, the birth defects from cyclopamine (including a one-eyed "Cyclops" appearance), results from disrupting the hedgehog pathway.

That story offers more testimony to the high value of the lowly fruit fly to cancer research, said Scott. "If you track the whole picture from beginning to end, what began as a basic science study about how body segments formed in fly larvae, led by a logical, stepwise process to the discovery of the most common cause of human cancer," and perhaps to possible treatments for cancer.



             
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