Berlin-based researchers from the Max Delbrück Center and Charité - Universitätsmedizin have unveiled the crucial role of the p53 gene in the development of ulcerative colitis (UC), offering potential new therapeutic strategies to halt the disease’s progression toward cancer. The findings, published in Science Advances, highlight p53’s function in controlling cell proliferation and suggest novel diagnostic tools for early intervention.
Ulcerative Colitis and Its Cancer Risk
Ulcerative colitis, a chronic inflammatory bowel disease that affects approximately five million people globally, significantly increases the risk of developing colon cancer. The condition affects the epithelial “crypts” lining the large intestine. These crypts, which contain stem cells essential for tissue maintenance and repair, enter a state of rapid proliferation during injury. However, in UC patients, these cells become trapped in what scientists refer to as a “regenerative state,” preventing them from maturing and functioning normally. This triggers a toxic cycle of excessive stem cell activity, worsening the disease.
The study, led by Kimberly Hartl, a graduate researcher at the Berlin Institute for Medical Systems Biology (MDC-BIMSB) in collaboration with Charité, links the malfunction of the p53 tumor suppressor gene to this defective repair process. Professor Michael Sigal, head of the Gastrointestinal Barrier, Regeneration, and Carcinogenesis lab at MDC-BIMSB, explained that p53 regulates the cell cycle and facilitates DNA repair. In its absence, epithelial crypt cells remain in a constant state of proliferation, impairing colon function and increasing cancer risk.
Potential for Early Detection and Treatment
Current diagnostic methods, such as colonoscopies, often identify precancerous lesions in UC patients only after visible changes occur, making removal difficult. However, the study suggests that targeting aberrant cells earlier, even before such lesions are detectable, could prevent cancer development. “This research offers a first step toward molecular tools that allow physicians to identify defective cells much earlier,” Sigal noted.
To explore the disease mechanisms further, the researchers created three-dimensional organoid models of the colon from mouse stem cells. These organoids allowed the team to simulate UC-related cell behavior and study how p53 influences the repair process. They observed that cells lacking p53 displayed increased glucose metabolism, relying heavily on glycolysis for energy. Conversely, when p53 was functional, it suppressed glycolysis, enabling cells to exit the regenerative state and return to normal function.
Targeting Metabolic Pathways to Halt Disease Progression
The researchers tested treatments that interfere with glycolysis on the organoids, finding that cells without the p53 gene were more susceptible to these interventions than healthy cells. “Organoids help us identify agents that target specific metabolic pathways, pointing toward potential new therapeutics for selectively eliminating mutated cells,” Hartl explained.
The next phase of the research will focus on transferring these findings to human studies. The team aims to develop simple diagnostic methods to detect p53-defective cells in colon tissue. Sigal emphasized that these advancements could lead to clinical trials designed to selectively target and eliminate abnormal cells, potentially lowering cancer risks in UC patients.
“This approach could revolutionize treatment by enabling us to kill defective cells before they become cancerous, offering new hope to patients at high risk,” Sigal added.
References:
1. Hartl, K., et al. (2024). p53 terminates the regenerative fetal-like state after colitis-associated injury. Science Advances. doi.org/10.1126/sciadv.adp8783.
(Input from various sources)
(Rehash/Ankur Deka/MSM)