In their latest publication, a team of researchers with the University of California, Riverside and the University of Notre Dame have revealed a new explanation for how ovarian cancer spreads (or metastasizes). The researchers used electron microscopy and live imaging to study the cellular activities that are associated with successful metastasis. As a primary ovarian tumor metastasis, it sheds both single cells and clusters of cells, which are called multicellular aggregates (MCAs) into the pelvis and abdomen. One of these activities is the expression of a group of proteins, which are called cadherins. Cadherins help cells to bind together and since they also enable cancer cells to anchor to new sites within the body, it may actually be possible to disrupt the metastasis if researchers can block the cadherin-mediated binding (UC Riverside, 2017).
Mark Alber, a distinguished professor of applied mathematics at the University of California, Riverside, and M. Sharon Stack, a Kleiderer-Pezold professor of biochemistry and director of Notre Dame Harper Cancer Research Institute, led the research program.
The researchers wanted to study the exact manner in which metastasis occurs, so they quantified the interactions between three-dimensional models of the abdomen wall and epithelial ovarian cancer (EOC). The researchers were able to show that when EOC cells received a type of cadherin protein called N-cadherin (or Ncad), which occurs in EO tumors, they were then able to penetrate the abdomen wall and attach to it. The researchers were also able to show that the MCAs that were dispersed prior to the invasion as a large cohort of cells and cell to cell junctional integrity (or single-cell attachment) was needed for metastasis to occur (UC Riverside, 2017).
Mark Alber said that unlike results observed in other cancers, ovarian cancers do not appear to need to follow a leader cell for collective cell invasion to occur.
"Interestingly, co-culture of Ncad-expressing cells with cells expressing E-cadherin (Ecad) did not promote invasion of the Ecad-expressing cells, demonstrating that Ncad-expressing cells do not simply lead the way for other cell populations to follow," Stack added.
The importance of Ncad in the metastasis of ovarian cancer is emphasized by the findings. The findings also provide rationalization to support the preclinical studies that used Ncad-blocking molecules as a form of therapy to stop or slow down the metastatic anchoring of EOC.
The research team plans to use the results to continue studying cancer cell invasion through the development of computational models. These future investigational studies will also use samples by patients that will be provided from research partners from the City of Hope in Duarte, CA, and combined with modeling and experimental approaches to gain new insights into the cellular mechanism of the metastasis of ovarian cancer (UC Riverside, 2017).
Why Ovarian Cancer is Difficult to Detect Early
Even with new breakthrough studies that demonstrate how ovarian cancer might spread, it is still one of the most difficult cancers to detect during its earliest stages, when it is also the easiest to combat. The three primary reasons why ovarian cancer is so difficult to treat early are: 1) It usually spreads before detection; 2) Limited screening technology; and 3) Limited treatments.
Everyone is filled with dread when they learn that they have a diagnosis of cancer, but for women who are diagnosed with ovarian cancer, that fear is even greater. A large majority of women diagnosed with the disease will die within 5 years following diagnosis. Part of the reason for this high mortality rate is that women don't normally receive their diagnosis until their ovarian cancer has already reached stage III or stage IV, at which point the cancer is very difficult, if not impossible, to cure. In fact, over 70 percent of ovarian cancer diagnoses are already in the late stages (Friedman, Sutphen, & Steligo, 2012). Of those women who are diagnosed within stage I, their chance of survival is at least 93 percent. The high survival rate is because cancer tumors are usually cured through surgical removal. Unfortunately, these cases of early-stage ovarian cancer are almost always discovered by accident, usually in the event of preemptive surgery where the ovaries and fallopian tubes have been removed because of risk factors, such as the BRCA1 and BRCA2 gene mutations.
If the chance for survival is so great with early stage ovarian cancer, then why can’t the cancer be detected sooner? Two of the primary reasons behind the late detection are poor screening options and confusing symptoms.
To date, there are not many reliable screening methods, other than symptom referral and the CA-125 test that can detect ovarian cancer at stage I. Unfortunately, research has just not discovered any screening methods that are cost-effective unless a woman has a very high risk factor, such as immediate family members (mother, daughter, sister) with ovarian cancer or the BRCA1 or BRCA2 gene mutations.
Another reason that so few women have their ovarian cancer detected early is that it has many subtle symptoms that are common to menopausal or menstruating women. Symptoms like bloating, fatigue, and abdominal pain may be easily overlooked for menstruation, menopause, urinary issues, or digestive problems. While these are common symptoms of everyday issues, a physician should be notified if the symptoms seem particularly new or occur for several days, and cannot be attributed to other health issues.
A pelvic exam is one screening method for detecting ovarian cancer. The National Cancer Institute recommends that all women over the age of 18 have a transvaginal ultrasound and a CA-125 blood test between every 6 months and every 12 months. A Pap smear may also help detect ovarian cancer. Though a Pap smear cannot test for ovarian cancer directly, it may uncover complications in the fallopian tubes that may be due to ovarian cancer.
Unfortunately, even the most experienced gynecologist can miss even the most advanced stage of ovarian cancer in a typical pelvic exam. Generally, by the time a gynecologist can feel ovarian cancer through a pelvic exam, the cancer is already in an advanced, difficult-to-treat stage. However, combined with CA-125 testing or transvaginal ultrasounds, a pelvic exam is much more effective at detecting ovarian cancer during earlier stages (Morris & Gordon, 2010).
Cancer antigen-125 (CA-125) is a particular protein that gets produced and released into the bloodstream by ovarian cells. The concentration is released at a higher level by cancerous ovarian cells than by normal ovarian cells. The results are expressed as U/ml. Any number greater than 35 U/ml is said to be an elevated CA-125 reading and may point to ovarian cancer. Unfortunately, elevated CA-125 levels are not reason enough to diagnose a woman with cancer as increased amounts are also associated with other issues, such as endometriosis, benign cysts, and pregnancy (Morris & Gordon, 2010).
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Friedman, S., Sutphen, R., and Steligo, K. (2012). Confronting Hereditary Breast and Ovarian Cancer. The John Hopkins University Press. Baltimore, Maryland.
Morris, J.L. & Gordon, O.K. (2010). Positive Results: Making the Best Decisions When You’re at High Risk for Breast or Ovarian Cancer. Prometheus Books. Amherst, New York.
University of California - Riverside. (2017, June 27). Study sheds light on how ovarian cancer spreads: Long-term goal is to develop treatments that prevent cancer cells from attaching to new sites during metastasis. ScienceDaily. Retrieved July 5, 2017 from www.sciencedaily.com/releases/2017/06/170627152615.htm