Chronic colitis can cause long-lasting molecular changes in colon stem cells that may increase the risk of tumor growth, according to a study published in Nature and announced on Mar. 29.
The findings are significant because they offer new insight into why patients with inflammatory bowel disease (IBD) face a higher risk of colorectal cancer, even after inflammation has resolved. The research suggests that the underlying changes in stem cells persist for more than 100 days after recovery from colitis, potentially lowering the threshold for malignant growth if an oncogenic mutation occurs.
Researchers used mouse models to track individual colon stem cells and found these cells retain an “epigenetic memory” of inflammation well after apparent recovery. A new assay called SHARE-TRACE revealed this memory is driven by increased activity of the AP-1 transcription factor and greater chromatin accessibility at certain sites, priming some stem cells for enhanced tumor outgrowth following mutations. "Assay results revealed that, while the transcriptome largely returns to baseline following recovery, the epigenome retains a persistent scar ('memory') for more than 100 days after recovery in the mouse model," researchers said.
The study observed only a small subpopulation of recovered tissue's stem cells—about 9.2% compared to 1.6% in controls—showed high AP-1 accessibility. Tumors induced in mice with previous colitis were significantly larger than those in control animals, suggesting altered epigenetic states give microscopic tumors a growth advantage rather than increasing their number.
Treatment with an AP-1 inhibitor reduced median tumor size by about 40%, indicating potential therapeutic value targeting these pathways rather than just addressing active inflammation. Researchers also found FOX transcription factors help stabilize AP-1 binding at memory sites, which could further inform future therapies or monitoring strategies.
These results suggest that long-term monitoring of epigenetic signatures might one day help identify IBD patients at higher cancer risk before tumors develop.
