“A long-standing question in cancer biology is ‘Do tumors arise from specific cell types’?” says lead author Craig A. Micchelli, Ph.D., assistant professor of developmental biology. “We asked what happens when the Apc gene is specifically disabled in fruit fly intestinal stem cells, and we observed that the mutant cells proliferate rapidly to create tumors. Our studies demonstrate that adult stem cells in the intestinal tract of fruit flies can function as a cell of origin for tumorigenesis.”
The study was published in the July issue of the journal Development.
In the gut of mature fruit flies, a population of primordial cells, called stem cells, exists to maintain the gut lining. When cells lining the intestinal tract die or are sloughed off, stem cells divide to produce replacements for the lost cells. Normally, just a couple thousand stem cells reside in a fruit fly’s gut and divide as needed to keep the gut healthy.
When the researchers selectively knocked out the Apc gene in these cells, they saw that the cells divided rapidly, forming masses of cells that protruded into the gut interior. These tumor-like masses had characteristics very like those of adenomas of the human gastrointestinal tract. Adenomas are benign tumors that can become malignant.
The Apc gene is often missing in people with the hereditary colon cancer syndrome familial adenomatous polyposis. Without surgery to remove all or part of the colon, colon cancer is virtually inevitable in those with Apc loss. The incidence of this type of cancer ranges from 1 in 7,000 to 1 in 22,000. Mutations in Apc are also detected in many spontaneous colon cancers. Colon cancer is the second-leading cause of cancer-related death in the Western world.
“Given its central role in tumorigenesis, we wanted to know where and when Apc is required,” Micchelli says. “We have developed a system in fruit flies that allows us to precisely manipulate gene function in individual cells of the gastrointestinal tract, so the stage was set to ask whether Apc had a specific function in intestinal stem cells.”
The researchers showed that Apc is needed to regulate stem cell proliferation in the fruit fly gut. Loss of Apc function short-circuits regulation, increasing the number of cells even though there is no physiological need for new cells. Apc is known to be part of a complex of several proteins in cells that destroys other proteins. Without Apc, these proteins go on to activate molecular pathways in the cell that promote cell proliferation.
“The fruit fly now provides a powerful genetic model system that can be used to study the earliest steps of gastrointestinal tumorigenesis,” Micchelli says. “The system can also be used to identify new genes that suppress the rapid proliferation caused by loss of Apc. Such genes constitute novel drug targets capable of retarding tumor growth at a very early stage.”
Lee WC, Beebe K, Sudmeier L, Micchelli CA. Adenomatous polyposis coli regulates Drosophila intestinal stem cell proliferation. Development 2009 Jul;136(13):2255-64.
Funding from Pew Scholars Program in the Biomedical Sciences, the Stem Cell Research Foundation, the American Cancer Society and Washington University School of Medicine supported this research.
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