Stanford scientists have found that retinoic acid curbs the development of colorectal cancer, deciphering a complex interaction between the vitamin A metabolite, gut bacteria and immune-related inflammation. The hope is to use these insights to prevent or treat colorectal cancer.
They induced intestinal tumors and intestinal inflammation in mice. Along with colleagues from the University of California, Berkeley, they used quantitative mass spectroscopy to inspect the retinoic acid levels in the mice’s intestinal tissue, according to a statement. The mice with cancer had “significantly lower” retinoic acid levels than the mice who only developed inflammation. This is because they made less of a protein that synthesizes retinoic acid and more of a protein that degrades it than the mice with intestinal inflammation.
The researchers then looked into controlling the cancer’s development by manipulating retinoic acid levels in the mice’s intestinal tissue.
"When we increased the amount of retinoic acid in the intestine, either by supplementing the animal with retinoic acid or by blocking the activity of the degradation enzyme, we were able to dramatically reduce the tumor burden in the animals," said Dr. Edgar Engleman, a professor of pathology and of medicine at Stanford, in the statement.
As for human studies, the team examined stored tissue samples from people who either had ulcerative colitis, a chronic inflammatory condition, or colorectal cancer associated with the condition. Their findings echoed those from the mice: the cancerous colorectal tissue had lower levels of the retinoic acid-synthesizing protein than tissue that was inflamed. But they also found that patients without chronic inflammation showed similar levels of the synthesis protein.
Targeting bacteria known to cause local inflammation, the scientists dosed mice with antibiotics, which tamped down tumor formation and prevented the change in retinoic acid levels observed in mice with colorectal cancer and in human tissue. The researchers also found that patients with higher levels of the retinoic acid-degrading enzyme did not live as long as patients with lower levels.
"We found that bacteria, or molecules produced by bacteria, can cause a massive inflammatory reaction in the gut that directly affects retinoic acid metabolism," Engleman said in the statement. "Normally retinoic acid levels are regulated extremely tightly. This discovery could have important implications for the treatment of human colorectal cancer."
"It's become very clear through many studies that chronic, smoldering inflammation is a very important risk factor for many types of cancer," Engleman said. "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. Ultimately we hope to determine whether our findings could be useful for the prevention or treatment of colorectal cancer."