Researchers from the Max Delbruck Center and Charite – Universitatsmedizin Berlin present key findings on the function of the p53 gene in ulcerative colitis. In this newly published study in Science Advances, there is likely a target for a future therapeutic intervention to reduce cancer risk in patients with UC.
Led by graduate student Kimberly Hartl, the team probed the role of the p53 tumor suppressor gene in UC. An inflammatory bowel disease that afflicts approximately five million people worldwide. A risk of colon cancer is associated with UC. Their findings point to a new approach to halt disease progression.
Professor Michael Sigal, senior author of the study, said that drug treatment now can target the aberrant cells in those patients at risk of developing cancer. “We could potentially get rid of them early before any cancer occurs,” he said.
Ulcerative colitis primarily affects the large intestine, particularly regions called “crypts.” These crypts contain stem cells, as well as other cell types. That work together to keep the colon healthy by absorbing nutrition and producing mucus. When injured, epithelial crypt cells go into “repair mode.” These cells proliferate rapidly to heal the colon injury. Unfortunately in UC patients, they often do not leave this regenerative state, resulting in few mature cells. This dearth of cells stimulates further stem cell proliferation in a vicious circle.
Hartl’s study linked this faulty repair mechanism to an inactivated p53 gene, which has a critical role in regulating the cell cycle and repairing DNA. Sigal clarified, “If there is no p53, cells remain in a proliferative state.”
Whereas the existing methods, including colonoscopies, have been able to identify visible precancerous lesions. Their removal can be anything but easy. It is now possible that this research may usher in less invasive diagnostic tools which would also be able to identify abnormal cells before even visible changes have taken place.
They established a three-dimensional model for colon organoids using mouse stem cells to study the repair process. The investigators work with experts in DNA and RNA sequencing, proteomics, and metabolomics. In a series of experiments to explore how p53 influences cell behavior.
They discovered that p53-free organoid cells remained in this regenerative state and metabolized glucose at a higher rate. Conversely, activated p53 depressed glucose metabolism and favored the return of cells to health. Treatment of organoids with compounds interfering with the glycolysis process linked to glucose metabolism revealed that the absence of p53 made these cells more sensitive to such treatment.
The findings will be applied to humans, say the researchers. They’ll be searching for less complicated ways of finding defective p53 cells in colon tissue. Says Sigal, “Once we have a method to identify these cells. We can perform clinical studies to selectively kill them. And analyze whether this lowers cancer risk.”
ANI
