Although rapidly dividing aberrant stem cells are a major cause of cancer, a new study by Washington University School of Medicine scientists indicates that mature cells also play a key role in initiating the disease. The finding (“Metaplastic Cells in the Stomach Arise, Independently of Stem Cells, via Dedifferentiation or Transdifferentiation of Chief Cells”), published in Gastroenterology, could cause a major change in thinking about the origins of the disease.

The team reports that mature cells have the ability to revert back to behaving more like rapidly dividing stem cells. However, when old cells return to a stem cell–like status, they can carry with them all of the mutations that have accumulated to date, predisposing some of those cells to developing into precancerous lesions.

“Spasmolytic polypeptide-expressing metaplasia (SPEM) develops in patients with chronic atrophic gastritis due to infection with Helicobacter pylori; it might be a precursor to intestinal metaplasia and gastric adenocarcinoma. Lineage tracing experiments of the gastric corpus in mice have not established whether SPEM derives from proliferating stem cells or differentiated, post-mitotic zymogenic chief cells in the gland base. We investigated whether differentiated cells can give rise to SPEM using a non-genetic approach in mice. Mice were given intraperitoneal injections of 5-fluorouracil, which blocked gastric cell proliferation, plus tamoxifen to induce SPEM,” write the investigators.

“Based on analyses of molecular and histological markers, we found SPEM developed even in the absence of cell proliferation. SPEM therefore did not arise from stem cells. In histologic analyses of gastric resection specimens from 10 patients with adenocarcinoma, we found normal zymogenic chief cells that were transitioning into SPEM cells only in gland bases, rather than the proliferative stem cell zone. Our findings indicate that SPEM can arise by direct reprogramming of existing cells—mainly of chief cells.”

“As scientists, we have focused a good deal of attention on understanding the role of stem cells in the development of cancers, but there hasn’t been a focus on mature cells,” said senior investigator Jason C. Mills, M.D., Ph.D., a professor of medicine in the Division of Gastroenterology. “But it appears when mature cells return back into a rapidly dividing stem cell state, this creates problems that can lead to cancer.”

The work, in mice and in human stomach cells, also raises questions about how cancer cells may evade treatment. Most cancer therapies try to halt cancer growth by stopping cells from rapidly dividing. Such treatments typically attack stem cells but would not necessarily prevent mature cells from reverting to stem cell–like status.

“Cancer therapies target stem cells because they divide a lot, but if mature cells are being recruited to treat injuries, then those therapies won’t touch the real problem,” noted first author Megan Radyk, a graduate student in Mills’ laboratory. “If cancer recurs, it may be because the therapy didn’t hit key mature cells that take on stem cell–like behavior. That can lead to the development of precancerous lesions and, potentially, cancer.”

Studying mice with injuries to the lining of the stomach, the researchers blocked the animals’ ability to recruit stem cells in the stomach. They focused on the stomach both because Dr. Mills is co-director of Washington University’s NIH-supported Digestive Disease Center, and because the anatomy in the stomach makes it easier to distinguish stem cells from mature cells that perform specific tasks. Even without stem cells, the mice developed a precancerous condition because mature stomach cells reverted back to a stem cell state to heal the injury.

Analyzing tissue specimens from 10 people with stomach cancer, the researchers found evidence that those same mature cells in the stomach also had reverted to a stem cell–like state and had begun to change and divide rapidly. Dr. Mills and colleagues want to find drugs that may block the precancerous condition by preventing mature cells from proliferating and dividing.

“Knowing these cells are leading to increased cancer risk may allow us to find drugs to keep mature cells from starting to divide and multiply,” Dr. Mills said. “That may be important in preventing cancer not only in the stomach and GI tract but also throughout the body.”