



Discovering commonality among disease states is no easy task, but it is an essential part of developing therapies that could have a much broader impact on the population. This strategy has been most difficult for cancer, which confusingly to some degree, is a collection of diseases grouped under one moniker. However now, investigators at Washington University School of Medicine (WUSM) in St. Louis have demonstrated that mature cells in the stomach sometimes revert to behaving like rapidly dividing stem cells and that process may be universal, regardless of the organ. Moreover, the WUSM scientists found that when some tissues respond to certain types of injury, mature cells seem to get younger and begin dividing rapidly, creating scenarios that can lead to cancer.

Findings from the new study were published recently in The EMBO Journal, in an article entitled “Regenerative Proliferation of Differentiated Cells by mTORC1-Dependent Paligenosis.”

“When we began the war on cancer in the 1970s, scientists thought all cancers were similar,” explained senior study investigator Jason Mills, M.D., Ph.D., a professor of medicine in the division of gastroenterology at WUSM. “It turned out cancers are very different from one organ to another and from person to person. But if, as this study suggests, the way that cells become proliferative again is similar across many different organs, we can imagine therapies that interfere with cancer initiation in a more global way, regardless of where that cancer may appear in the body.”







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Older cells may be dangerous because when they revert to stem cell-like behavior, they carry with them all the potential cancer-causing mutations that have accumulated during their lifespans. However, because mature cells in the stomach, pancreas, liver, and kidney all activate the same genes and go through the same process when they begin to divide again, the findings could mean that cancer initiation is much more similar across organs than scientists have thought. That could support using the same strategies to treat or prevent cancer in a variety of different organs.

Studying cells from the stomach and pancreas in humans and mice, as well as mouse kidney and liver cells, and cells from more than 800 tumor and precancerous lesions in people, the research team found that when tissue is injured by infections or trauma, mature cells can revert to a stem cell state in which they divide repeatedly. And along the way, those cells all activate the same genes to break down the mature cells and help them begin to divide again.

“First, we saw a massive increase in the activity of genes associated with cell degradation,” observed lead study investigator Spencer Willet, Ph.D., a research associate in Dr. Mills laboratory. “Then, the cell's growth pathway senses that degradation and releases nutrients that then activate cell growth pathways and allow the mature cells we studied to proliferate.”

“We showed that differentiated cells in diverse organs become proliferative via a shared program. The metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9, and finally reactivate mTORC1 and re-enter the cell cycle,” the authors wrote. “Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective Gnptab−/− mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach.”

The researchers further explained that paligenosis—the process in which mature cells begin dividing again—appears similar to apoptosis—the programmed death of cells as a normal part of an organism's growth and development—in that it seems to happen the same way in every cell, regardless of its location in the body.

“Nature has provided a way for mature cells to begin dividing again,” Dr. Mills remarked, “and that process is the same in every tissue we've studied.”

The investigators believe the discovery that cells in different organs go through the same process to become proliferative could lead to new potential targets for cancer treatment because the factors that initiate tumors could be the same in multiple organs.

“If you were to compare this reprogramming of cells to tearing down a building and putting something new in its place, the slow way to go would be to remove and then replace each brick, one at a time,” Dr. Mills concluded. “What we're seeing is that nature is smarter than just running the building program in reverse. Instead, there is a wrecking ball program: When an old cell begins to divide again, a program runs to clear things out and then rebuild, and the same program runs in every tissue we've analyzed.”























