Johns Hopkins researchers say there is growing
evidence that stem cells gone awry in their efforts to
repair tissue damage could help explain why long-term
irritation, such as from alcohol or heartburn, can create a
breeding ground for certain cancers.
At the heart of their argument, outlined in the Nov.
18 issue of Nature, are two key chemical signals,
called Hedgehog and Wnt ("wint"), that are active in the
stem cells that repair damaged tissue. Recently and
unexpectedly, the signals also have been found in certain
hard-to-treat cancers, supporting an old idea that some
cancers may start from normal stem cells that have somehow
gone bad.
Over the last 10 years, researchers have found
examples of these so-called cancer stem cells — the
cells within a tumor that are capable of regrowing the
tumor — in certain malignancies of the blood, breast
and brain. In most cases, however, it's not clear whether
these cancer stem cells came from the tissue's normal,
primitive stem cells or from the tissue's mature cells.
"Cancers associated with chronic irritation may be a
good setting in which to determine whether stem cells are
the starting place of tumors," said Phil Beachy, professor
of molecular biology and
genetics in Johns Hopkins' Institute for Basic
Biomedical Sciences and a Howard Hughes Medical Institute
investigator. "Successful therapy depends on targeting the
cells that drive cancer's growth and its spread, so we have
to know which cells are important."
Chronic irritation damages tissues —
Helicobacter infection in the stomach leads to ulcers, for
example, and chronic acid reflux (heartburn) erodes the
lining of the esophagus. That damage triggers a repair
process that requires tissue-specific stem cells to gather,
multiply and eventually replace the damaged cells.
However, if recurring irritation and damage prevent
the repair's completion, those helpful stem cells, in
theory, could accumulate mutations that push their growth
out of control. Beachy and longtime collaborators and
co-authors Sunil Karhadkar and David Berman suggest that
chronic irritation might facilitate trapping of stem cells
in a state of perpetual activation, and subsequent genetic
or other changes in the cells may send them over the
edge.
"Normal stem-cell self-renewal is a tightly regulated
process, so the question is how and whether such regulation
is circumvented in cancer," Beachy said.
Beachy said the place to start looking is the activity
and regulation of Hedgehog and Wnt, which are best known
for their roles in embryonic development, because recent
studies show they are key regulators of self-renewal in at
least some of the body's normal tissue stem cells and are
active in numerous cancer types.
"If these stem cells are the starting point of some
cancers, multiple genetic and other changes may be required
to trap the stem cell during chronic irritation, and
perhaps many more changes to get the rapid growth of
cancer," Beachy said. "We need to figure out what those
changes might be."
Hedgehog activity has been found in certain cancers of
the lung, brain, stomach, esophagus, skin, pancreas,
bladder, muscle and prostate. Similarly, Wnt activity has
been tied to certain cancers of the colon, liver, blood,
bone and lung.
In experiments at Johns Hopkins and elsewhere,
blocking Hedgehog and Wnt in laboratory-grown cancer cells
and in animals has been shown to kill cancer cells, so the
pathways are potential targets for anti-cancer drugs. The
researchers caution that Hedgehog and Wnt blockers could
affect normal processes that use these signals, including
normal tissue repair, although short-term studies in mice
have not yet found toxic side effects, Beachy said.
Authors of the article are Beachy, Karhadkar and
Berman, all of Johns Hopkins. The authors' research is
supported by the Howard Hughes Medical Institute, the
National Institutes of Health, the Prostate Cancer
Foundation and the Flight Attendant's Medical Research
Institute.
GO TO