Finding a needle in a haystack
Searching for biomarkers of ovarian cancers
By Dawn Stapleton
Ovarian cancer is sometimes called the disease without a voice. Because the number of long-term survivors is small, there are few former patients to build awareness, disseminate educational information, or garner support for a cure.
The disease causes more deaths than any other cancer of the female reproductive system and is fourth in mortality for all women's cancers. Its symptoms can mimic those of minor illnesses, which make them easy to dismiss: 75 percent of ovarian cancers are diagnosed at relatively advanced stages – with a five-year survival rate ranging from 5–35 percent.
In contrast, 95 percent of women whose cancer is found before it has spread outside the ovary survive a minimum of five years, making early detection a crucial part of reducing ovarian cancer deaths.
Ronny Drapkin, MD, PhD, along with his colleagues in the Center for Molecular Oncologic Pathology, is working toward this end. They are in search of biomarkers, or proteins, specific to ovarian cancer that show up in the blood or urine at the onset of the disease.
"Right now in ovarian cancer research, there is more work to do than there are hands to do it," explains Dr. Drapkin. "It is a vital time during which we need to invest in hiring good people and acquiring the resources necessary to better understand the development and progression of this disease. Ultimately, we have to translate observations into clinically useful tools that can make meaningful advances in early detection of the disease and in the development of novel therapeutics."
Dr. Drapkin and colleagues have identified a trio of proteins present in women with ovarian cancer that could be tested for in blood or urine. These are: HE4, or human epididymis protein 4, SLPI (secretory leukocyte protease inhibitor), and elafin. Though it's still too early to tell, these proteins look like they may also be therapeutic targets for the disease.
During ovulation the oocyte, or egg cell, matures and bursts out of the ovary in a mini-explosion. Often, the surrounding cells are damaged and may get trapped in surrounding tissue known as the stroma. This creates cortical inclusion cysts (CICs), which can also form as a result of aging. These cysts are susceptible to malignant changes that can lead to cancer.
Illustration by John DiGianni
Finding answers
Dr. Drapkin discovered these proteins' connection to ovarian cancer while he was studying whether tumor development is related to ovulation. Traditionally, events that stop ovulation for a time – childbearing, breastfeeding, or taking birth control pills – are known to help prevent the disease or reduce risk by 15–30 percent. (See related story: Broken bones, the Pill, and ovarian cancer.) Conversely, early puberty or late menopause is associated with increased risk. So Dr. Drapkin asked, what happens during ovulation that predisposes normal tissue to become cancerous tissue?
During the menstrual cycle, an egg cell bursts out of the ovary in a mini-explosion, creating a natural inflammatory reaction. Cells in the immediate area die, while others on the periphery of the explosion survive but are damaged. Occasionally, these altered cells become trapped in the stroma (supportive tissue within the ovary), where they form cysts called cortical inclusions (see illustration above).
Dr. Drapkin is working with a three-dimensional tissue system to understand the biology of cortical inclusions and how they arise during ovulation. These cysts are present in most ovaries and their incidence increases with age. Normally, they are benign. However, researchers theorize that sometimes the damaged cells inside the cyst contain altered DNA that produces changes that may lead to cancer. The team found that both the cysts and tumors produce the same set of three proteins, HE4, SLPI, and elafin. Now, they are trying to determine how these proteins function after ovulation – during the healing of the ovary when the cysts and cancer are likely to form.
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