Mature Gut Cells Can Revert to a Stem-Like State and Fuel Colorectal Cancer, Study Finds

Colorectal cancer is the second leading cause of cancer death in the United States, and rates are rising rapidly in adults under 55. While stem cells have been identified as a significant driver of the disease, exactly what happens at the cellular level inside the gut has remained incompletely understood. A new study from Stevens Institute of Technology adds important detail to that picture—and points to a cellular mechanism that may help explain why colorectal cancers are so difficult to treat.

The study, published in Cell Death & Disease, focuses on Lgr5-positive stem cells, which play a central role in the constant renewal of the intestinal lining. "These stem cells are crucial for the rapid renewal of tissues of the intestinal lining," said senior author Ansu Perekatt. "They are rapidly dividing cells that give rise to the progenitor cells in order to constantly replace the lining of the intestine."

The intestine has a defined organizational structure. Lgr5-positive stem cells and their progenitor cells reside in small pocket-like structures called crypts, while the villi—tiny projections that line the small intestine and aid nutrient absorption—are composed of mature, specialized cells that have left the crypt and stopped dividing. Perekatt's team explored how colon tumors can originate in two distinct ways: a "bottom-up" process in which normal stem cells deep in the intestine mutate and turn cancerous, and a "top-down" process in which mature surface cells reprogram themselves, reacquiring stem-like behavior before becoming cancerous.

"Mature cells can sometimes reverse course and become stem-like again, especially after injury or when normal stem cells are lost," Perekatt explained. "A similar process can happen in colon tumors, where mature, already specialized cells can acquire what we call the de-novo stemness and regain stem cell-like behavior." 

In mouse model experiments, the team induced mutations in stem cells and observed that while the mutant stem cells were ultimately replaced by healthy ones, a subset of their progenitor cells became cancerous. Tumors arising from cells that acquired de-novo stemness also showed stronger survival mechanisms, including a capacity to protect themselves against oxidative stress. 

The findings carry direct implications for treatment. "If you are only treating the cells that become cancerous without targeting the cells that acquired the de-novo stemness, the cancer will likely come back," Perekatt said. "So it's really important to understand what causes this reversion to stemness, in order to develop new and effective therapies for colorectal cancers."