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Updated 11:50 AM October 25, 2007
 

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Discovery could aid search for stomach cancer origin

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.

A group of U-M 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 glands that line the lower portion of the stomach. This 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, a developmental biologist and senior author of a study that appears online in the journal Gastroenterology.

The epithelial cells that make up the millions of glands of the stomach constantly are turning over. Most of the mature functioning cells live only 20-60 days before being replaced by progeny of dividing resident stem cells. These stem cells not only are 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, the stem cells 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 Center for Organogenesis and is a professor in the Department of Cell and Developmental Biology at the 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 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 this form of 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 Qiao, a 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 effectively could be marked using a mouse model developed earlier in Gumucio's lab.

Just what specific role these progenitor cells may play in inflammation and cancer is not clear yet.

The researchers suspect the effort to understand stomach stem cells and their possible relationship to cancer will take many more twists and turns. 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 Ziel, Wendy McKimpson, Blair Madison, Dr. Andrea Todisco, Dr. Juanita Merchant and Linda Samuelson.

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