WIKIMEDIA, OPENSTAX UNIVERSITY In healthy individuals, chief cells, that are found at the base of corpus glands in the stomach, work as producers of digestive enzymes. However , if the gut goes through damage or genetic mutation, these cells have the ability to transform into stem cells that can lead to gastric cancer, based on a study published last week (June 5) in Nature Cell Biology .

“ This is actually the first definitive demonstration that a subset of key cells is cancer prone and can serve as the origin associated with gastric cancer, ” says study coauthor Nick Barker, who studies cancer and stem cells at A*STAR Institute of Medical Biology (IMB) in Singapore.

Still, the identity of gastric-cancer forming cellular material has been controversial, and not all researchers are convinced Barker’ s i9000 study has resolved the debate.

The long-standing theory in gastroenterology is that stem cells within the stomach arise in the isthmus, the region located around the core corpus glands. These cells migrate to the tops plus bottoms of the glands, replenishing lost cells and keeping homeostasis. Mutations in these stem cells, many scientists think, can lead to precancerous lesions, such as metaplasia (abnormal change within tissue).

In recent years, however , a new hypothesis provides emerged. Based on the observation of spasmolytic polypeptide-expressing metaplasia (SPEM), James Goldenring at Vanderbilt University and colleagues suggested that this specific type of metaplasia in the stomach arises from main cells that converted (or “ transdifferentiated” ) in to a different cell type. “ It’ s very difficult to find out it happening, and people have questioned whether this is actually happening in humans, ” Barker says. “ That it is controversial. ”

For example , in 2015, a team of researchers led by Timothy Wang, a gastroenterologist from Columbia University reported that when they used a diphtheria toxin to kill off chief cells in the bellies of mice, mutations to the remaining cells still offered rise to metaplasia and cancer. “ His bottom line was that… chief cells cannot be the cell-of-origin of that malignancy, ” Barker says.

To further address this particular question, Barker and colleagues created a mouse model by which they discovered Lgr5 , a gene typically expressed in adult stem cells across numerous tissues, selectively labelled only a subset of chief tissues (around 40 percent). This calls into question the particular conclusions of Wang’ s study, Barker says, since that experiment only ablated chief cells expressing Lgr5 , meaning others were left undamaged, making it impossible to come to the conclusion that chief tissues did not give rise to metaplasia.  

Through extra experiments, Barker’ s team discovered that these Lgr5- labelled chief cells could give rise to cellular regeneration when exposed to injury. In addition , when the researchers launched mutations associated with gastric cancer, these chief-cells-turned-stem-cells led to metaplasia. “ Under normal conditions, these cells behave as differentiated chief cells, whereas if you damage the tissue, these are activated and they function as stem cells, ” says research coauthor Marc Leushacke, a research scientist at the IMB.

“ I wasn’ t surprised by the choosing because they basically support everything that we’ve found for the last fifteen years, ” Goldenring, who did not take part in this research, tells The Scientist. “ This gets us back to the point of recognizing that will chief cells are the origins of SPEM. ”

Wang, however , is not convinced. More data are essential to definitively say the chief cell hypothesis is true, he admits that. For example , it is important to investigate the entire gland, not just the bottom (in the chief cell zone), to prove that the stem tissues don’t come from higher up in the glands, such as within the isthmus zone, where stem cells are typically located. This individual adds that it would be useful to see a more detailed time span of the process, along with markers to clarify where the regeneration is  predominantly  originating from.   Ablation studies would also be helpful, where either the isthmus stem cells or main cells are blocked, and then re-investigate if the effects nevertheless occur.

Others take pause with the authors’ claim that their study shows that gastric cancer originates from main cells. “ They claim that this is a cell-of-origin of gastric cancer, but there’ s no gastric cancer with this paper at all, ” says Stuart McDonald, a come cell biologist at Barts Cancer Institute in the Oughout. K. who was not involved in the study. “ So the design they use, it forms a metaplasia, but as far as I realize, they don’t go to cancer. ”

Goldenring states that a definitive link between metaplasia in the stomach plus gastric cancer is still lacking in both animal and human studies. A primary reason for this, he adds, is that researchers have yet to generate a true model of gastric cancer in mice.

Settling this debate could have important implications for both the avoidance and treatment of cancer. For example , Barker says, if researchers can be sure that chief cells are the cell-of-origin for gastric cancer, they can try to elucidate the mechanisms that result in cancer, and potentially stop those from happening that individuals who are more likely to develop it. In addition , Wang says, “ we think that the stem cells are expanded, early on, simply by carcinogenic injury, and this is potentially an early biomarker designed for gastric cancer risk, for example. ”

Scientists agree that this debate is far from over, and that a lot more work is needed to fully understand how gastric cancer arises. “ I think the paper serves a purpose in that it helps in order to drive  interest  in the stem cell biology in the tummy, ” McDonald says, “ because we’ re obviously just at the beginning of understanding what’ s going on. ”