Stem cell discovery could aid search for how stomach cancer begins
U-M researchers identify rare population of progenitor cells in mouse
stomachs, paving way for learning origins of tumors
ANN ARBOR, MI – Scientists have identified and described stem cells
specific to several tissues and organs of the body — key master cells
that give rise to the specialized cell types characteristic of that
organ. But to date, it hasn't been possible to pinpoint functioning
stem cells in the stomach, either in laboratory animals or people.
In this image of the mouse antral stomach, the bright green cell is a
gastric progenitor cell. The cell has activated the mouse villin
promoter, which drives expression of the green fluorescent protein
(GFP). Cells that express GPF can be seen easily under the microscope
and can be isolated by specialized cell sorting machines. This green
progenitor cell will divide to give rise to all of the other cells
that make up the flask-like cells that make up this portion of the
stomach. The ability to regenerate the glands is a stem cell
property.
Now, a group of University of Michigan Medical School researchers has
succeeded in finding and manipulating a population of cells that
strongly resemble stem cells in the stomachs of mice. They have been
able to show that these cells, which they call "gastric progenitor
cells," can give rise to all the different types (or lineages) of
specialized cells needed to form the functional stomach glands that
line the lower portion of the stomach. This property of "multi-
lineage potential" is considered a key stem cell property.
"The identification of these progenitor cells will not only aid in
our understanding of normal cell turnover in the stomach, but could
potentially open some new and exciting doors in our investigation of
the origins of gastric cancer," says Deborah Gumucio, Ph.D., a U-M
developmental biologist and senior author of a study which appears
online ahead of print in the journal Gastroenterology.
The epithelial cells that make up the millions of glands of the
stomach are constantly turning over. Most of the mature functioning
cells live only 20 to 60 days before being replaced by progeny of
dividing resident stem cells. These stem cells are not only a
constant source of new cells, but they represent an important
reservoir for repair of damage to the stomach caused by injury or
inflammation. In addition, since the stem cells are the longest-lived
of the gastric cells, it is thought that these are the only cells
that live long enough to accumulate the multiple mutations that can
cause cancers. For these reasons, the ability to identify and
manipulate stomach progenitor cells has been an important goal for
decades.
"Before this work, we knew that stem cells existed in the stomach,
but we had no way to precisely identify them," says Gumucio, who
directs the U-M Center for Organogenesis and is a professor in the
Department of Cell and Developmental Biology at the U-M Medical
School.
"There were no effective markers or tags that we could use to clearly
discriminate the stem or progenitor cells from other cells. Now, for
the first time, we have the experimental tools to ask important
questions, like, `Does stomach cancer really arise from mutations in
this progenitor cell population?'
Stomach cancer is a major cancer killer outside the United States. It
is the most common cause of cancer deaths in much of East Asia and
Latin America. In the United States, it is estimated that 21,260
people will be diagnosed with stomach cancer and 11,210 will die of
it in 2007.
There are several types of stomach cancer, but one very prevalent
type, called intestinal-type gastric adenocarcinoma, progresses
through a defined series of steps. Initially, the insult is an
inflammatory one, usually through infection by an acid-tolerant
bacterium called Helicobacter pylori. The chronic inflammation
eventually leads to changes in the character of the surrounding
stomach cells and ultimately, over several years, to tumors. These
tumors often arise in one particular area of the stomach.
Interestingly, the progenitor cells that the Gumucio lab has
identified are concentrated precisely in this tumor-prone area.
To spot and watch the progenitor cells at work, Gumucio's team, under
lead author Xiaotan T Qiao, Ph.D., a U-M Medical School research
associate, had to get past the hurdle that has deterred the search
for stomach stem cells so far – finding effective markers, which act
like identification tags to make tracing possible. Qiao was able to
identify the gastric progenitor cells and later explore their
behavior because the cells could be effectively marked using a mouse
model developed earlier in Gumucio's lab.
"Since gastric cancers often occur in the context of inflammation, we
were interested to determine whether these progenitor cells are
affected by inflammatory conditions," says Qiao.
"We were amazed to see that though these cells are normally very
quiescent, that is, they don't divide, inflammatory signaling
proteins such as interferon gamma provide a potent stimulus for
multiplication of these cells."
Just what specific role these progenitor cells may play in
inflammation and cancer is not clear yet.
"Are these cells good guys, bad guys or innocent bystanders? We just
don't know," Gumucio says. They could be cells that are in some ways
predisposed to being cancer cells. Alternatively, they could be
important reservoirs for repair of damage caused by injury or
inflammation. In that case, having more of them could be a good
thing, she says.
"These are probably not the only stem-like cells in the stomach,"
adds Qiao. "This must be a subset of such cells, but they certainly
represent an interesting subset, given their location in the stomach
and their response to inflammation.
additional new markers to find other stem-like cells in the stomach.
The researchers suspect the effort to understand stomach stem cells
and their possible relationship to cancer will take many more twists
and turns. Any therapies or prevention methods resulting from this
early research are years away. An important next immediate step is to
look in human stomachs to see if this type of stem or progenitor cell
can be identified.
In addition to Gumucio and Qiao, other U-M authors of the study
include Joshua W. Ziel; Wendy McKimpson; Blair B. Madison, Ph.D.;
Andrea Todisco, M.D.; Juanita L. Merchant, M.D., Ph.D., and Linda C.
Samuelson, Ph.D.
Journal citation: Gastroenterology (2007), doi:
10.1053/j.gastro.
The research was funded by the National Institutes of Health and a
Munn Idea Grant from the University of Michigan Comprehensive Cancer
Center.
The University of Michigan through its Office of Technology Transfer,
has licensed the commercial distribution of the villin Cre mouse
model, developed by the Gumucio laboratory and used in this study, to
genOway, a laboratory mouse supplier. The mice are also available
through Jackson Laboratories, and have been distributed to hundreds
of investigators worldwide.
Written by Anne Rueter
http://www.med.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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