2009 Turning Point

The search for the source of serous ovarian cancers: a medical detective story
by Robert Levy

Ronny Drapkin, MD, PhD 

Atop every list of how to deal with cancer is the importance of early detection. Regular screenings – self exams and those conducted by clinicians – are the surest way of detecting tumors in their initial stages, when they're easiest to treat.

For nearly every type of cancer, that advice is perfectly sound. Cancer is like a brush fire, best stamped out or contained when it first forms, before it has a chance to spread.

But there are some cancers that don't have a known formative stage, that seem to burst onto the scene in an advanced, malignant state, having already overrun a wide swath of tissue. Such tumors are notoriously difficult to treat, their sudden emergence a sign of their ferocity.

One of the most common of these tumors is known as serous ovarian cancer. Less than a quarter of the cases are detected at an early stage, a figure reflected in the survival rates for the disease.

Serous cancers occur on the surface of the ovaries and surrounding membranes, often in several places, making them impossible to eliminate by surgery alone. The introduction of drugs like platinum and taxanes have lengthened the survival of many patients, but cure rates have not substantially improved.

"When these cancers are diagnosed they seem to be everywhere at once," says Ronny Drapkin, MD, PhD, of Dana-Farber's Women's Cancers Program (WCP), who is leading some of the research into the tumors' origins. "Their discovery at an advanced state of development limits our ability to treat them effectively. That's why it's so important to identify 'precursor' cells from which the tumors arise."

Cancer, in a nutshell

Ronny Drapkin, MD, PhD, and his team direct the "living" bank of ovarian tumor tissue at Dana-Farber. 

Over the course of modern cancer research, scientists have mapped out what might be called "The Genesis of a Cancer," the step-by-step process by which some tumors form in the lining – or "epithelial" layer – of tissues and organs.

It begins with a completely normal cell, anywhere in the body, whose DNA is damaged by exposure to a chemical, radiation, or the normal stresses of life. The cell then may repair the damage or kill itself to prevent the defect from being passed on to its offspring. If the damage is not repaired and occurs in a gene responsible for cell growth and division, the cell may be a cancer precursor, behaving oddly in one or two respects, but not immediately dangerous. Only after it acquires additional damage, or genetic mutations, does it acquire the classic characteristics of cancer – proliferation, burrowing into tissue, siphoning blood and nutrients from other cells, refusing to die on time, and demonstrating an ability to spread to other parts of the body.

This process means that scientists should be able to identify a continuum for the development of virtually any tumor they come across – the normal tissue where it originated, the quirky precursor cells that follow, the invasive and restless cells that mark it as cancer. In the case of high-grade serous ovarian cancer, however, the trail has been cold: for years, scientists couldn't find a trace of the cells that preceded full-blown tumors.

"We had to ask ourselves whether this disease is a fundamentally different entity from other types of cancer, or whether we had been looking for precursor cells in the wrong place all along," says Christopher Crum, MD, director of women's and perinatal pathology at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC), who sought to unravel the mystery of the condition's origins.

'Carpetbagger' cancers

A discovery by Christopher Crum, MD, and his colleagues offers insight into how serous cancers arise and spread, and how they might be stopped. 

A key clue lay outside the ovaries themselves. The fallopian tubes, the narrow chutes that carry fertilized eggs to the uterus, also can be the site of origin of serous cancers. Can advanced serous cancers of the ovary actually be decoys – the result of cancer cells that left the fallopian tubes and settled in the ovary?

The evidence is pointing in that direction. First, the ovary and fallopian tubes are next-door neighbors – the broad end of the fallopian tube cupping the ovary in fingerlike strands called fimbria – so cancer cells don't have to travel far to go from one to the other. Second, ovarian and fallopian tube cancer cells look identical under a pathologist's microscope and behave quite similarly.

If high-grade serous ovarian cancers (HGSOCs) are in fact masquerading fallopian tube tumors, then women diagnosed with HGSOC would be likely to have cancerous lesions, or sections of diseased tissue, on their tubes. Traditionally, however, pathologists haven't examined the entire fallopian tube, concentrating on the more accessible central section of the tube.

In 2005, Dr. Crum and his colleagues developed a special technique for inspecting the "fimbriated" end of fallopian tubes – the portion, adjacent to the ovaries, with slender tendrils like the top of a sea anemone. Using this technique, called SEE-FIM (for "Sectioning and Extensively Examining the Fimbriated end"), they conducted a top-to-bottom exam of fallopian tubes that had been removed as a preventive measure from women with an inherited risk for ovarian cancer.

In a succession of studies, Dr. Crum's team found that some of the tubes harbored early cancers, almost always in the fimbriated end, the end closest to the ovary. "This was strong evidence that the source of many serous carcinomas in the pelvic region, including the ovary, is the fimbriated – or 'distal' – end of the fallopian tube," Dr. Crum says. "These are tumors that seem to grow best outside their birthplace."

The evidence may have been strong, but it wasn't yet definitive. Then, in 2006, Dana-Farber's Alexander Miron, PhD, used advanced gene-sequencing technology to show that the early cancers in the fallopian tube had the same genetic mutations as the tumors elsewhere in the pelvis.

In search of precursors

Having found the fallopian tubes to be the "nursery" of many high-grade serous ovarian cancers, researchers could focus on their ultimate quarry, figuring out how and where normal cells become precancer and then cancer.

"That was the 'Wow' moment," said Dr. Crum. "We now had a marker for these types of serous cancers and a pathway by which they develop."

Here, a surprise was in store. Studies had 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 Dana-Farber and Brigham and Women's researchers tested normal-looking fallopian tissues, they found that about half the samples also had the p53 signature.

"That was the 'Wow' moment," Dr. Crum says. "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, further mutations produce cancers within the fimbrial tissue of the fallopian tube, and the cancers migrate to the ovary."

The discovery doesn't imply 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 women are menstruating, an egg pops out of an ovary in what has been described as a "mini explosion." The 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.

Evidence assembled by Women's Cancers Program scientists suggests that many ovarian cancers originate in the finger-like ends of the fallopian tubes.
Illustration by Lee Whale 

"The p53 signature is like a sign telling us that the cell's self-repair system is down," Dr. Crum says. If this theory is correct, then women who have fewer children and have children at an older age – and thereby have a higher lifetime number of menstrual cycles – would be more likely to develop precancerous cells. Research by Dr. Crum, in association with Judy Garber, MD, MPH, director of the Friends of Dana-Farber Cancer Risk and Prevention Clinic, and Shelley Tworoger, PhD, an epidemiologist at Brigham and Women's Hospital (BWH), found this to be the case.

As for why serous cancers often take root in the ovary rather than their "native soil" in the fallopian tube, scientists speculate that the ovarian terrain is somehow more hospitable for the fledgling tumor cells.

Future directions

Knowing the ultimate source of many serous ovarian tumors raises some intriguing possibilities for treatment. Understanding how precancerous cells become cancerous may suggest ways of disrupting the process before malignancies develop. Being able to detect cancers in their earliest stages – or identify tissue where tumors are likely to form – could dramatically raise survival rates for the disease.

WCP researchers have assembled a team with the expertise to reach those goals. The team includes Dr. Drapkin and his colleagues who are developing model systems of fallopian tube cells and their precancerous descendents; Dr. Miron, who conducts genetic analyses of cell and tissue samples; Dr. Crum, who heads the pathology efforts; Dr. Garber, who studies cancer risk factors; Tan Ince, MD, PhD, of BWH, who directs a live cell bank; Ross Berkowitz, MD, director of Gynecology and Gynecologic Oncology at BWH and Dana-Farber, Ursula Matulonis, MD, director of Gynecologic Medical Oncology at Dana-Farber, and Michael Muto, MD, and Colleen Feltmate, MD, of the Gynecologic Oncology program at DF/BWCC, who treat patients and lead clinical trials of new therapies.

"The pieces are in place, both technological and scientific, to get a handle on the development of serous cancers of the ovary, and to use those abilities to design and test more effective treatments," Dr. Drapkin remarks. "We're in a position to bring treatment of this disease into the age of targeted therapies."

2009 Turning Point