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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
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
"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."
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
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.
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
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.
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.
"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.
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