Researchers Identify Vital Gene for Preserving Gastrointestinal Health During Cancer Treatment
The stem cells in the gut divide so fast that they create a completely new population of epithelial cells every week. However, this quick cell division is also why radiation and chemotherapy wreak havoc on the gastrointestinal systems of patients with cancer, as such therapies target rapidly dividing cells. Scientists at the University of North Carolina (UNC) School of Medicine and the UNC Lineberger Comprehensive Cancer Center found that a rare type of stem cell is immune to radiation damage, due to high levels of a gene called Sox9.
The discovery, which was made in mice and published by Roche et al in Gastroenterology, could lead to new ways to protect the gastrointestinal systems of patients with cancer before they receive treatment. Such a preventive measure could allow patients to receive higher treatment doses to more aggressively attack cancer cells.
“Not only do we show that Sox9 is responsible for making and maintaining these rare ‘reserve’ stem cells, but also that the gene has a radioprotective impact on the intestine after radiation damage,” said Scott Magness, PhD, Associate Professor of Medicine, Cell Biology, Physiology, and Biomedical Engineering at UNC.
Reserve Stem Cells
For decades, scientists have known that “reserve” stem cells exist, possessing all of the properties of regular stem cells—except for rapid division. Regular stem cells divide quickly under normal conditions to supply the gut with enough cells to keep the intestinal lining in working order. But during cancer treatment, the DNA of normal stem cells is mutated so much that the cells die through apoptosis, which causes damage to the intestinal lining. This is why patients with cancer experience severe gastrointestinal side effects during treatment.
When cancer therapy kills the regular stem cells, the reserve stem cells replenish the gut lining. Why or how these cells do so is unclear.
Kyle Roche, a fourth-year graduate student and first author of the Gastroenterology article, said, “It hasn't been proven, but there's strong evidence suggesting that when the normal ‘active’ stem cells are dead and gone, the reserve cells move into the newly opened space, wake up, and begin to divide to replenish the epithelial lining.”
Mouse Models
Using mice, researchers conducted an analysis of single cells that naturally express Sox9 to check whether they had an expression pattern consistent with reserve stem cells. They found that some cells had strong stem cell signatures. Then, Sox9 was removed in the mice to see whether reserve stem cells relied on Sox9 to live. The researchers found that animals without Sox9 lacked this reserve stem cell population and that these mice did not recover when exposed to radiation.
“If Sox9 is not present, then reserve stem cells are not made, and the animals are much more sensitive to radiation damage,” said Mr. Roche, who noted that humans also have Sox9 in their intestines.
Dr. Magness pointed out, “If we can figure out the mechanisms that Sox9 uses to control reserve stem cells, then theoretically, we could develop an agent to protect cancer patients against the gastrointestinal side effects of chemotherapy and radiation.”
More immediately, Mr. Roche said it should be possible to increase Sox9 levels in human epithelial cells and test whether these cells would survive following DNA damage caused by radiation or chemotherapy.
“If so, then this would put Sox9 on the board as a therapeutic target for pharmaceutical agents that can protect the intestine during radiation therapy,” he said. “We think Sox9 carries a lot of promise in advancing our understanding of how to preserve the intestinal health of cancer patients during treatment.”
Dr. Magness is the corresponding author of the Gastroenterology article.
This study was supported by the National Institutes of Health and the UNC Center for Gastrointestinal Biology and Disease.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
