Researchers at the University of Stanford School of Medicine have cast more light of the role of retinoic acid deficiency in bowel cancer development, determining that the presence of the vitamin A metabolite plays an important role in the suppression of colorectal cancer.
Analyzing retinoic acid levels in the gut is problematic due to the speed at which the metabolite breaks down in the presence of light. However, the team – in conjunction with researchers at the University of California Berkeley – developed a new method of using quantitative mass spectrometry to measure levels of retinoic acid in the gut. The research team used the new technique to measure retinoic acid levels in the guts of mice with induced gut inflammation and colorectal tumors.
The mice were treated with a chemical that caused inflammation in the intestines and one which stimulated the growth of tumors. The team found that mice with colorectal tumors had significantly lower levels of retinoic acid in the gut than mice with inflammation in the intestines without tumors. The team also found that mice with tumors were producing lower levels of proteins that synthesize retinoic acid and had four times the levels of a protein that degrades the metabolite.
The findings led to the team conducting a study to try to bring retinoic acid levels back within the normal range to determine what effect this had on the development of tumors. When retinoic acid levels were returned to normal – by either artificially increasing levels of retinoic acid in the gut or by blocking the activity of the protein that degrades retinoic acid – the tumor burden in the animals reduced. The tumor burden increased when retinoic acid activity was inhibited.
The research team also assessed the levels of synthesis and degradation proteins in tissue samples from human patients with ulcerative colitis and colorectal cancer and found the results reflected what they had observed in mice. Patients with higher levels of retinoic acid in the gut – measured indirectly from protein levels – tended to fare better.
Certain bacteria can cause inflammation of the gut, which it was hypothesized affected retinoic acid levels. Since chronic inflammation of the gut has been linked to the development of colorectal cancers, the researchers thought it may be possible to reduce the formation of tumors by reducing inflammation. The researchers treated mice with broad-spectrum antibiotics to kill the bacteria known to cause inflammation and noticed the formation of tumors slowed.
Edgar Engleman, MD, professor of pathology and of medicine at Stanford University School of Medicine said “We found that bacteria, or molecules produced by bacteria, can cause a massive inflammatory reaction in the gut that directly affects retinoic acid metabolism.” The team also discovered that retinoic acid blocks or slows the development of cancer by activating a specific type of CD8 T cell. Those T cells attack and kill off cancer cells. The team demonstrated that the reduction in retinoic acid reduced the extent to which these CD8 T cells were activated, which led to an increase in the tumor burden in mice.
The research into the role of retinoic acid deficiency in bowel cancer development could lead to new ways of treating colorectal cancer in humans and help to prevent the development of tumors. As Engleman explained, “Now that we’ve shown a role for retinoic acid deficiency in colorectal cancer, we’d like to identify the specific microorganisms that initiate these changes in humans.” Engleman went on to say, “Ultimately we hope to determine whether our findings could be useful for the prevention or treatment of colorectal cancer.”