December 10, 2004

Bone marrow cells found to cause gastric cancer in mice

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Sachiyo Nomura, M.D., Ph.D., a visiting scientist, left, and Jim Goldenring, M.D., Ph.D., collaborated on a paper recently published in Science.
photo by Dana Johnson

Bone marrow cells found to cause gastric cancer in mice

For the last decade, James R. Goldenring and colleagues have been in pursuit of the cell source of stomach cancer. They have a surprising new lead — cells from the bone marrow can populate the stomach lining and give rise to gastric cancer in mice.

The findings, published Nov. 26 in Science, “create a new paradigm for how cancer can occur,” said Goldenring, M.D., Ph.D., professor of Surgery and Cell & Developmental Biology.

The expectation, he said, was that stomach stem cells were the cancer culprit. The discovery that bone marrow-derived cells can cause gastric cancer in mice suggests that investigators need to be casting a wider net for the cell sources of cancer.

“It's provocative, and now we want to find ways to examine whether this is happening in humans,” Goldenring said.

The work could lead to screening tests and early interventions for gastric cancer, a leading cause of cancer deaths in the world.

Goldenring and longtime collaborator Timothy C. Wang, M.D., now at Columbia University, have been tracking a particular “metaplasia” — a change in the cells lining the body of the stomach. This metaplasia occurs in mice infected with Helicobacter felis, the cat equivalent of Helicobacter pylori. In humans, H. pylori infection causes up to 95 percent of gastric cancer.

“So our question has been, is this metaplasia the pre-cancerous cell?” Goldenring said. “If we can identify a specific cell population that in itself is not cancerous but then becomes cancerous, we can develop screening tests, which do not exist for gastric cancer.”

An analogy, he said, is Barrett's esophagus, a condition in which a change in the cells lining the esophagus has been linked to the development of esophageal adenocarcinoma. Patients with Barrett's esophagus are routinely screened for progression to adenocarcinoma. Goldenring and colleagues have been trying to make a similar link between the stomach metaplasia and gastric cancer.

The current studies do just that.

“These findings seal the deal that this metaplasia is pre-cancerous, at least in the mouse,” Goldenring said.

The investigators believe that the metaplasia following Helicobacter infection is initially a repair mechanism. But in the presence of continued infection and inflammation, bone marrow-derived cells appear to populate the stomach lining and “mimic the metaplasia that's already under way,” Goldenring said.

And then, he said, instead of “turning off,” like the normal reparative metaplasia would, “these cells don't turn off. They keep dividing, and there's a higher chance that they will degenerate and go on to neoplasia.”

To show that bone marrow-derived cells populate the stomach mucosa and then become cancerous, the group transplanted “marked” bone marrow from a donor mouse into a mouse whose bone marrow had been killed. The donor marrow cells could be detected because they turned blue (in the presence of certain chemicals) or glowed green.

Although the group used multiple methods to show that donor bone marrow populated the stomach mucosa, the work “will be controversial,” Goldenring said. It is the first demonstration that bone marrow-derived cells can take up residence and expand to repopulate a tissue, he said.

Goldenring emphasized that the findings apply only to mice, and so far only to the particular mouse strain that the team studied. Still, he said, “this is a possible pathway that we have to think about now for how cancers arise.”

To look for evidence that bone marrow-derived cells contribute to gastric cancer in humans, co-author and gastric surgeon Sachiyo Nomura, M.D., Ph.D., a visiting scientist in Goldenring's lab, will turn to her native Japan.

Stomach cancer is the leading cancer type in Japan, where the high incidence has prompted routine endoscopic screening of the population.

When Nomura returns to her faculty position in the Department of Gastrointestinal Surgery at the University of Tokyo, she will be seeking bone marrow transplant patients who, on routine endoscopic screening, have evidence of metaplasia. The perfect patient, she said, would be a woman who received bone marrow from a male donor — marrow that could be identified by its Y chromosome.

Regardless of whether the cell source is a bone marrow-derived cell or a stomach cell, the bigger implication of the work is “that an identification of a metaplasia can lead you to the cancer,” Goldenring said. The findings will open the door for studies aimed at identifying “pre-neoplastic markers” for stomach cancer screening.

The research was supported by the Vanderbilt-Ingram Cancer Center GI SPORE grant, a Veterans Affairs Merit Review, and a Funderburg Research Scholar Award in Gastric Biology Related to Cancer.