Researchers have found that a drug used in the treatment of mental illness can promote the fitness of healthy gut stem cells, making them less susceptible to cancer. Scientists are launching a clinical trial after that discovery. They are planning to recruit individuals that carry mutations in a gene called APC; these mutations are thought to cause bowel or colon cancer in almost all carriers. The findings have been reported in Nature.
Intestinal stem cells with the APC mutation are able to outcompete stem cells without the mutation, and these mutant cells can then grow uncontrollably, leading to cancer. In this study, the researchers found that the mutant intestinal stem cells release signals that sabotage healthy gut stem cells.
"We have uncovered the very first steps in the development of bowel cancer. We found that following the occurrence of a mutation in a key gene that regulates stem cells in the intestine, these cells turn into cheaters that actively suppress the normal cells in the environment," said senior study author and professor Louis Vermeulen, Group Leader at the Centre for Experimental Molecular Medicine at Amsterdam UMC.
"This is a totally new concept as it was always thought that mutant cells that can turn into cancer simply proliferate faster or are resistant to cell death. But our findings indicate that cells on their way to a full malignancy can actively suppress the stem cells in the vicinity to gain a competitive edge. This is a concept we refer to as super-competition."
Importantly, the researchers found that lithium, which is often used in the treatment of mental illness, can prevent the mutant cells from forming tumors. The drug appears to make the healthy cells disregard the signals from the mutant stem cells.
Individuals with a genetic disorder called familial adenomatous polyposis (FAP) have mutations in the APC gene. FAP patients develop non-cancerous bowel growths called polyps and adenomas, and most get bowel cancer between age 35 and 45. The clinical trial will test whether lithium has a preventive effect on that cancer in ten young adult FAP patients that will be treated with lithium for eighteen months. The researchers will investigate whether lithium can prevent polyp growth, how it impacts mutant stem cells, and whether it's safe for these patients. Positive results will likely lead to larger trials.
"Our clinical trial may reveal that lithium can be used to prevent cancer development in FAP individuals. But what is also important is that this trial can establish a proof of concept that manipulating competition between mutant cells and normal cells can be manipulated in such a way that the healthy cell outcompetes the mutant cells," said first study author and graduate student Sanne van Neerven. "This is a novel strategy for cancer prevention and could be applied to many heritable cancer syndromes involving different mutations and organs, but more research is warranted in this area."
"Around one percent of bowel cancers are caused by familial adenomatous polyposis. This may seem like a small number, but in the UK alone this means that over 400 people are diagnosed with bowel cancer caused by FAP every year. The only treatment option available for people with FAP is major surgery to remove the entire colon, which can be life-altering and unfortunately cannot guarantee that cancer won't develop. The launch of a clinical trial thanks to this incredible research will offer real hope to people that there could be a simple way to prevent bowel cancer in the future," noted Dr. Helen Rippon, Chief Executive at Worldwide Cancer Research.