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Might some advanced cancers of the ovary actually be decoys of the disease's origins – the result of cancer cells that left the fallopian tubes and settled in the ovary? The evidence is pointing in that direction, according to recent research by Dana-Farber/ Brigham and Women's Cancer Center (DF/BWCC) scientists.
Some cancers don't have a known formative stage. They seem to appear in an advanced, malignant state, having already overrun a wide swath of tissue. Such tumors are notoriously difficult to treat. One example is serous ovarian cancer, which is detected at an early stage less than 25 percent of the time.
Dana-Farber and Brigham and Women's scientists have found the fallopian tubes are likely to be the "nursery" of many high-grade serous ovarian cancers. They're now working to understand how the switch from normal cell to cancer cell occurs and when the migration to the ovary takes place.
As they began exploring these questions, they quickly discovered a surprise. Studies have shown that early cancers in the lining of the fallopian tube contain high levels of a protein called p53. The accumulation of the protein, caused by a breakdown in the p53 gene, was dubbed "the p53 signature." When the researchers tested normal-looking fallopian tissues, they found that about half the samples also had the p53 signature.
"That was the 'wow' moment," says Christopher Crum, MD, director of women's and perinatal pathology at the Dana-Farber -Brigham and Women's Cancer Center. "We now had a marker for these types of serous cancers and a pathway by which they develop: normal cells acquire mutations in the p53 gene, further mutations produce cancers within the fimbrial tissue of the fallopian tube, and the cancers migrate to the ovary."
The discovery doesn't mean that every woman whose fallopian tubes carry the p53 signature will develop serous cancers: In fact, only a small percentage of them will. But it has enabled scientists to construct a narrative about how such cancers arise and spread, and how they might be stopped.
Every month when a woman is menstruating, an egg pops out of her ovary in what has been described as a "mini explosion." The resulting tear in the ovary is mended by a blend of hormones and other proteins from the immune system. On rare occasions, this fix-it crew may inadvertently meddle with the DNA in nearby cells, such as those in the fimbriated ends of the fallopian tubes. One gene that's susceptible to such changes is p53, whose job is to repair damaged DNA. A mutation can render the p53 protein useless, leaving the cell vulnerable to further mutations that could make it cancerous. The mutation also causes p53 to loiter too long within the cell - hence the p53 signature in precancerous cells.
"The p53 signature is like a sign telling us that the cell's self-repair system is down," says Crum. If this theory is correct, then women who have fewer children, and thereby have a higher lifetime number of menstrual cycles, would be more likely to develop precancerous cells. Research by Crum and his colleagues found this to be the case.
Understanding the origins of serious ovarian cancers may suggest ways of disrupting the process early on. "The pieces are in place, both technological and scientific, to get a handle on the development of these cancers, and to use those abilities to design and test more effective treatments," says Ronny Drapkin, MD, PhD, of Dana-Farber's Women's Cancers Program, who is leading some of the research into the disease.
– Rob LevyRobert_Levy@dfci.harvard.edu
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