Mutations in the two genes ARID1A and PIK3CA in mice led to the formation of clumps of ovarian clear cell carcinoma cells.
Image credit: Ron Chandler/UNC
The researchers, from the University of North Carolina (UNC) at Chapel Hill, hope their findings will open new avenues to better treatments and much-needed diagnostic screens.
Ovarian cancer affects the ovaries, the reproductive organs responsible for producing eggs and female hormones in women.
Ovarian cancer is hard to detect, because the symptoms - such as feeling bloated and experiencing changes in appetite - are often mistaken for other conditions. There is also no effective diagnostic screen for early detection of ovarian cancer.
When ovarian cancer is found early, it can be highly treatable, and the 5-year survival rate in such cases is over 90%. But unfortunately, only 1 in 5 cases are found early, leaving the majority of patients to learn that their cancer has spread, is at an advanced stage that is hard to treat and their prognosis is stark.
While the pace is slow, the situation is gradually improving. Thirty years ago, the survival rate for women diagnosed with ovarian cancer in the US was 10-20%. Nowadays, it is nearer 50%.
According to the American Cancer Society (ACS), a woman's risk of getting ovarian cancer during her lifetime is about 1 in 75, and her lifetime chance of dying from the disease is about 1 in 100.
The ACS estimate that in 2015, about 21,290 women in the US will receive a new diagnosis of ovarian cancer and about 14,180 women will die from the disease.
New mouse model depicts aggressive ovarian cancer just as it presents in humans
The senior author of the new study is Terry Magnuson, the Sarah Graham Kenan Professor and chair of UNC's Department of Genetics. He says the new model portrays an extremely aggressive form of ovarian cancer - ovarian clear cell carcinoma - just as it presents in women.
Not all mouse models of human conditions are able to portray them as accurately as they occur in humans. But the model that Prof. Magnuson and colleagues have developed is based on genetic mutations found in human cancer samples.
Prof. Magnuson says they used the mouse model to show how mutations in two genes - ARID1A and PIK3CA - interacted to trigger the aggressive ovarian cancer:
"When ARID1A is less active than normal and PIK3CA is overactive, the result is ovarian clear cell carcinoma 100% of the time in our model."
The team was also able to use the mouse model to show that BKM120, a drug that suppresses PI3 kinases - proteins that are involved in cancer cell growth, survival and proliferation - directly inhibited ovarian tumor growth and significantly prolonged the lives of mice.
BKM120 is currently undergoing human trials for the treatment of other cancers.
Two gene mutations interact to trigger aggressive ovarian tumor formation and growth
The study arose from previous work that found the ARID1A gene was highly mutated in several types of tumor, including ovarian clear cell carcinoma. But that work also found deleting the gene in mice did not trigger tumor formation or growth.
This is how the UNC team found the gene needed to interact with another gene, as Dr. Ronald Chandler, a postdoctoral fellow in Prof. Magnuson's lab, explains:
"We found that the mice needed an additional mutation in the PIK3CA gene, which acts like a catalyst of a cellular pathway important for cell growth. Too little expression of ARID1A and too much expression of PIK3CA is the perfect storm; the mice always get ovarian clear cell carcinoma. This pair of genes is really important for tumorigenesis."
Dr. Chandler says their research also "shows why we see mutations of both ARID1A and PIK3CA in various cancers, such as endometrial and gastric cancers."
The team also discovered that ARID1A and PIC3CA mutations were involved in overproduction of a protein that helps trigger inflammation. They say they do not know if inflammation causes ovarian clear cell carcinoma, but they do know it is important for tumor cell growth.
Speaking about the protein - Interleukin-6, or IL-6 - Prof. Magnuson says: "We think that IL-6 contributes to ovarian clear cell carcinoma and could lead to death. You really don't want this cytokine circulating in your body."
He suggests when they treated tumor cells with an antibody that targets IL-6, it inhibited cancer cell growth, so perhaps reducing levels of IL-6 could help patients, he adds.
The potential for new ways to diagnose ovarian cancer
The researchers say that while their work will help identify better treatment targets, it may also lead to new ways of diagnosing ovarian cancer.
Dr. Chandler says maybe they could find a biomarker that could be used to screen women. Perhaps there is a cell surface protein "downstream of ARID1A," he suggests, adding that:
"Right now, by the time women find out they have ovarian clear cell carcinoma, it's usually too late. If we can find it earlier, we'll have much better luck successfully treating patients."
The study was funded by the National Institutes of Health, with additional support from the ACS and the Ovarian Cancer Research Fund.
In March 2014, Medical News Today learned how scientists achieved another breakthrough by finding the genetic cause of a rare, aggressive ovarian cancer that most often strikes girls and young women.
In that study - which used groundbreaking genomic techniques - the international team found several strong links between a mutation in the SMARCA4 gene and a large majority of patients with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).