[D66] FYI: New Insights into Origin of Deadly Cancer

[Henk Elegeert]

New Insights into Origin of Deadly
Cancer<http://www.focushms.com/features/new-insights-into-origin-of-deadly-cancer/>
June 23, 2011

*Barrett’s esophagus, often a precursor to esophageal cancer, results from
residual, embryonic cells*

Researchers have discovered a new mechanism for the origin of Barrett’s
esophagus, an intestine-like growth in the esophagus that is triggered by
chronic acid reflux and often progresses to esophageal cancer. Studying
mice, the researchers found that Barrett’s esophagus arises not from mutant
cells in the esophagus but rather a small group of previously overlooked
cells present in all adults that can rapidly expand to cancer precursors
when the normal esophagus is damaged by acid.

This research will be published online in the June 24th issue of *Cell*.
<http://www.focushms.com/wp-content/uploads/2011/06/McKeon-cells1.jpg>

Embryonic cell precursors (green) of Barrett’s esophagus at the junction
between the stomach and esophagus (red). Image by McKeon lab.

Decades of cancer research tells us that most of the common cancers begin
with genetic changes that occur over a period of 15 to 20 years, in some
cases leading to aggressive cancers. However, for a subset of cancers that
appear to be linked to chronic inflammation, this model might not hold.

Barrett’s esophagus, which was first described by the Australian surgeon
Norman Barrett in 1950, affects two to four million Americans. In this
condition, tissue forms in the esophagus that resembles the intestinal
tissue normally located much farther down the digestive tract. As a result,
a person’s chances of developing a deadly esophageal adenocarcinoma increase
by 50- to 150-fold. Late stage treatment is largely palliative, so it is
important to understand how acid reflux triggers it in the first place.

Research from the laboratory of Frank McKeon<https://mckeon.med.harvard.edu/>,
Harvard Medical School professor of cell biology, together with Wa Xian, a
postdoctoral researcher at Brigham and Women’s Hospital and the Institute of
Medical Biology, Singapore, along with an international consortium including
Christopher Crum, director of Women’s and Perinatal
Pathology<http://www.obgynpath.org/gynpath/default.aspx> at
Brigham and Women’s Hospital, has shown that Barrett’s esophagus originates
from a minor population of non-esophageal cells left over from early
development.

For the past decade, McKeon and his laboratory have been using mouse models
to investigate the role of p63, a gene involved in the self-renewal of
epithelial stem cells including those of the esophagus. McKeon joined forces
two years ago with Wa Xian, an expert in signal transduction in cancer
cells, to tackle the vexing problem of the origin of Barrett’s esophagus.**

**

At that time, the dominant hypothesis for Barrett’s was* *that acid reflux
triggers the esophageal stem cells to make intestine cells rather than
normal esophageal tissue.  However, McKeon and Xian felt the support for
this concept was weak. Taking a different track, they studied a mouse mutant
lacking the p63 gene and mimicked the symptoms of acid reflux. As a result,
the entire esophagus was covered with a Barrett’s-like tissue that proved to
be a near exact match with human Barrett’s at the gene expression level.

The researchers were particularly surprised by the sheer speed with which
this Barrett’s esophagus appeared in the mice.

“From the speed alone we knew we were dealing with something different
here,” said Xia Wang, postdoctoral fellow at Harvard Medical School and
co-first author of this work.

Yusuke Yamamoto, a postdoctoral fellow at the Genome Institute of Singapore
and also co-first author, added that, “we just had to track the origins of
the Barrett’s cells back through embryogenesis using our markers from
extensive bioinformatics.”

In essence, the investigators tracked the precancerous growth to a discrete
group of leftover embryonic cells wedged between the junction of the
esophagus and the stomach–precisely where endoscopists have argued Barrett’s
esophagus begins. As predicted by the mouse studies, the researchers
identified a group of embryonic cells exactly at the junction between the
esophagus and the stomach in all normal humans. **

“Barrett’s arises from this discrete group of pre-existing, residual
embryonic cells present in all adults that seemingly lie-in-wait for a
chance to take over when the esophagus is damaged,” said McKeon. Added Xian,
“We know these embryonic cells have different gene expression patterns from
all normal tissues and this makes them inviting targets for therapies to
destroy Barrett’s before it progresses to cancer.”

The therapeutic opportunities of this work are potentially immense.

“We are directing monoclonal antibodies to cell surface markers that can
identify these precursor cells, so we may have a new opportunity to
intervene therapeutically and prevent Barrett’s esophagus in at-risk
patients,” said Wa Xian.

“Additionally,” noted McKeon, “we are cloning the stem cells for both these
precursors and for Barrett’s esophagus itself, and these should represent
critical targets for both monoclonal antibodies and small molecule
inhibitors.”

Finally, there is reason to believe that this unusual mechanism might apply
to a subset of other lethal cancers with unsure origins.

Crum noted that “some very aggressive cancers arise at junctions of two
tissues and these deserve closer scrutiny to get at their origins if we are
to surmount these diseases.”

This work was supported by the National Institutes of Health.
"

Henk Elegeert
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <http://www.tuxtown.net/pipermail/d66/attachments/20110626/1919bd49/attachment.html>