Cornell University researchers have discovered a likely origin of epithelial
ovarian cancer (ovarian carcinoma), the fifth leading cause of cancer death
among women in the United States.
Pinpointing where this cancer originates has been difficult because 70% of
patients are in advanced stages of disease by the time it is detected. Because
the origin of ovarian carcinoma development is unknown, early diagnostic tests
have so far been unsuccessful.
Some epithelial cancers are known to occur in transitional zones between two
types of epithelium (layers of tissue that line the body and organs and form
glands), while others originate in epithelial tissue stem cells. All organs have
the capacity for regeneration, which is done by adult stem cells located in
areas of each organ called stem cell niches.
Stem cell niche
With this knowledge, the researchers discovered a novel stem cell niche for
the ovarian surface epithelium in mice and showed that ovarian carcinoma
preferentially originates from stem cells found in that niche, according to the
study. This stem cell niche lies in a transitional area known as the hilum
region, a layer of cells that links the ovary to the rest of the body.
"We now know where these cells are located in mice, so we can look in humans
in those areas," said Alexander Nikitin, professor of pathology, leader of the
Cornell Stem Cell Program and the paper's senior author.
Andrea Flesken-Nikitin, a postdoctoral researcher in Nikitin's lab, is the
paper's lead author. The findings also provide a guide for scientists to look
for stem cell niches and sources of cancer in other transitional zones in other
organs, Nikitin added.
The researchers proved that stem cells from the hilum region were highly
prone to ovarian carcinoma, using the most current genetic research
The researchers first found that cells in the hilum region express a known
marker for stem cells, called ALDH1.
They then isolated ALDH1 positive cells, sequenced their genetic profiles and
found many markers previously reported for stem cells in other organs.
Fate of stem cells
One of these markers, LGR5, has been studied for intestinal stem cells by
other researchers who have bred special mice and developed an advanced method
that uses a fluorescent protein to follow stem cells.
The gene encoding the fluorescent protein is passed down from a stem cell to
each generation of daughter cells, thereby marking the lineage.
The technique "allows you to see the fate of stem cells over time," said
Using the method on the hilum cells, "we showed that cells from the hilum
area spread around the whole ovary."
Finally, the researchers micro-dissected ovary and hilum cells, inactivated
two tumour suppressor genes p53 and Rb1, whose pathways are commonly altered in
human aggressive ovarian carcinoma, and injected cells into the abdominal cavity
Very few tumours developed in the mice injected with ovary cells, but almost
all of the mice injected with hilum cells died after developing aggressive,
metastasizing cancers that were similar to human ovarian carcinomas.
In future work, the researchers will look for stem cells and sources of
cancer in transitional zones in the human ovary and other organs, such as the
stomach, rectum and uterine cervix.