Ovarian cancer kills an estimated 14,000 American women each year. The high mortality rate for women with ovarian cancer stems from a lack of early symptoms or screening methods for the disease. As a result, most ovarian cancer patients are diagnosed with advanced-stage disease as highlighted by the findings from the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, or PLCO trial, presented at the annual American Society of Clinical Oncology meeting June 4, 2011.
In addition to the PLCO trial, the National Cancer Institute has funded numerous aspects of ovarian cancer research, including studies as part of the Specialized Programs of Research Excellence, or SPORE. The ovarian cancer SPORE grants address the full range of prevention, early detection, and treatment of ovarian cancer.
Like other SPORE grants, the ovarian cancer SPOREs are designed to enable the rapid and efficient movement of basic scientific findings into clinical settings, as well as to determine the biological basis for observations made in individuals with cancer or in populations at risk for cancer.
In 2009, ovarian cancer SPORE grants were awarded to:
- Brigham and Women’s Hospital, Boston, Mass.
- Fox Chase Cancer Center, Philadelphia, Penn.
- Fred Hutchinson Cancer Center, Seattle, Wash.
- Mayo Clinic, Rochester, Minn.
- University of Texas, MD Anderson, Houston
The following is a highlight of work being conducted by scientists at the ovarian cancer SPORE program at Brigham and Women’s Hospital, which is a teaching affiliate of Harvard Medical School in Boston. Over the next several months, studies by investigators at other ovarian cancer SPORE groups will be featured.
Early precursor lesions to ovarian cancer arise in the fallopian tubes
Scientists at the ovarian cancer SPORE at Brigham and Women’s Hospital have found evidence that a majority of serous cancers, a lethal type of ovarian cancer, arise in fallopian tube fimbria, which are the fringed far ends of the fallopian tube, rather than on the surface of the ovaries.
Christopher P. Crum, M.D., of the Brigham and Women’s Hospital, and Ronny I. Drapkin, M.D., Ph.D., who is also affiliated with Dana-Farber Cancer Institute, have conducted additional studies that show serous cancers begin as precursor lesions in the fallopian tube fimbria that spread to the surface of the ovary, or shed into the peritoneal cavity. Serous cancer is often found in the ovaries, peritoneal cavity, and fallopian tubes. Until the emergence of these finding on the genesis of serous cancer, it was thought that all three sites represented independent sites of origin and risk.
Women with BRCA mutations have precursor lesions in fallopian tubes
Studies in the Crum laboratory found a small abnormal population of cells within fallopian tube biopsy samples taken from women with BRCA 1 or BRCA 2 gene mutations. BRCA gene mutations are associated with hereditary serous cancer; these women had their ovaries and fallopian tubes surgically removed as a preventative measure against this disease.
The scientists microscopically examined the entire inside lining of the fallopian tube and its fimbriated ends. Results of these biopsy sample studies showed that up to 15 percent of women with the BRCA gene mutation had small, predominately non-invasive tumors within the fallopian tube fimbria, while about 33 percent had pre-malignant precursor lesions, called the p53 signature.
The p53 signature is a benign-appearing population of secretory cells that are characterized by DNA damage, p53 gene mutations, and accumulation of the p53 protein, the latter of which can be detected by tissue staining, a method used to give contrast to the tissue or to highlight a particular feature.
One of the functions of the p53 gene is to block cell division when a cell has sustained DNA damage. However, if the p53 gene itself becomes disabled, damaged cells will proliferate and possibly lead to cancer. The scientists reasoned that the repeated cellular injury and repair of the fallopian tube fimbria, secondary to repeated ovulatory cycles, might cause the DNA damage that leads to the appearance of the p53 signature.
Women without cancer have precursor lesions in fallopian tubes
Next, the scientists tested to see if the p53 signature was present in fallopian tubes biopsy samples taken from women not genetically predisposed to cancer. Their studies demonstrated that fewer of these women (less than 5 percent) were diagnosed with cancer; however, nearly the same proportion, almost 33 percent, harbored a p53 signature. Some of these lesions were early molecular changes only; the damaged cells looked normal under the microscope.
“The significance of finding secretory cells that look normal, but are actually damaged at the DNA level, with wide-spread DNA damage and mutations, is that they likely represent precursor lesions to serous cancer,” said Crum. “Importantly, scientists have looked for a precursor to this cancer for a long time and never found it in the ovary.”
There are a number of implications that make these findings significant:
- From a clinical perspective, it warrants thorough analysis of all fallopian tubes, especially in women who have risk-reducing surgeries because they are at high-risk for serous cancer. This is already being implemented in many parts of the country and around the world.
- There is active discussion now about whether surgeons should consider simply removing the fallopian tubes or the just the fimbria in women at high-risk of developing serous cancer (BRCA gene mutation carriers).
- All basic and translational science on serous ovarian cancer has been based on using the ovarian surface epithelial cells as the starting point, i.e. the cell of origin. This new model warrants careful study of the fallopian tube epithelial cells and the development of models systems to do so.
Experimental models test precursor lesions to serous cancer
Work in the Drapkin lab is focused on the development of two experimental model systems to clearly define the p53 signature and to develop methods to test the hypothesis that this lesion may be the precursor to serous cancers.
The first model is a novel ex vivo cell culture system where primary fallopian tube cells are harvested directly from women who had their fallopian tubes removed for reasons unrelated to cancer. These cells are grown on special filters that enable them to mimic the behavior of tubal cells in vivo (inside of the living body).
“Using this system, we found that the secretory fallopian cells display a delayed ability to respond to DNA damage. The damage, as we expected, is probably a result of monthly ovulation, a known risk factor for ovarian cancer. The inability of these cells to repair their DNA damage in a timely manner potentially leaves them susceptible to the accumulation of additional mutations to their genes over time. Our work is now directed at deciphering the underlying mechanism of this behavior,” said Drapkin.
For the second model system, Drapkin’s group removed secretory cells from the fallopian tube ex vivo model and immortalized them, i.e. altered the cell’s genetic programming so they could divide indefinitely. These cells are now being used to study the biology of fallopian tube secretory epithelial cells to determine how genetic alterations contribute to tumor development in vitro and in vivo.
“Research has indicted that ovarian cancer is not a mutation-driven disease, rather, it is a disease of copy instability, i.e. the tumors show broad irregularities in the number of copies of a certain gene–too many, too few, or none at all. Using our new fallopian tube transformation system, in which we can genetically alter a cell by the introduction of defined genetic elements, we are in the position to figure out which alterations contribute to transformation and which may be simple bystander aberrations due to genomic instability,” said Drapkin.
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