Retinoic Acid Slows Colorectal Cancer Progression

Mice with colorectal cancer were found to have lower levels of a vitamin A metabolite in their gut, while patients with colorectal cancer who express high levels of a retinoic acid degrading-protein in their intestinal tissues had poorer survival rates in a recent study.

The study is the first to attempt to untangle the complexities involved between gut microorganisms, retinoic acid levels, and immune-related inflammation. The findings, published in Immunity, suggest new techniques to treat or prevent colorectal cancer in humans.

“The intestine is constantly bombarded by foreign organisms,” said senior study author Edgar Engleman, MD. “As a result, its immune system is a very complex. There’s a clear link in humans between inflammatory bowel disease, including ulcerative colitis, and the eventual development of colorectal cancer. Retinoic acid has been known for years to be involved in suppressing inflammation in the intestine. We wanted to connect the dots and learn whether and how retinoic acid levels directly affect cancer development.”

Although retinoic acid is essential for numerous processes of growth and development, it can be tricky to accurately detect levels of the metabolite in the body because it degrades quickly when exposed to light.

To address this issue, researchers used the quantitative mass spectrometry technique to measure the retinoic acid in the intestinal tissues of mice treated with 1 or both of 2 chemicals. One of the chemicals caused intestinal inflammation, while the other stimulated the development of colorectal cancer.

Mice treated with both of the chemicals developed intestinal tumors with 9 to 10 weeks of treatment. Mice treated with only the first chemical developed intestinal inflammation, but not cancer.

In the mice who developed colorectal cancer, researchers found they had significantly lower-than-normal levels of retinoic acid in their gut, compared with the other group who did not develop cancer.

Upon further investigation, researchers discovered the intestinal tissues of mice with cancer produced less of a protein that synthesizes retinoic acid, and approximately 4 times more of a protein that degrades retinoic acid, resulting in the rapid decrease of metabolite levels.

Researchers next wanted to explore whether increasing the levels of retinoic acid back to a more normal range could affect the progression of the disease.

“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,” Engleman said. “Conversely, inhibiting retinoic acid activity significantly increased the tumor burden.”

Although researchers investigated the levels of degradation proteins and synthesis in stored samples of intestinal tissue taken from ulcerative colitis or colorectal cancer patients associated with ulcerative colitis, they were unable to directly measure the retinoic acid levels since the samples were stored instead of freshly collected.

In human tissue samples, researchers did find some similarities to those seen in mice, such as the human colorectal cancer tissue having higher levels of the degradation protein, and lower levels of the synthesis protein, than those found in tissue that was only inflamed and not cancerous. Researchers also saw an inverse correlation in the amount of degradation protein and how long a patient lived.

This means high amounts of the degradation enzyme in the intestinal tissues of patients caused worse outcomes than those in patients with lower levels of the enzyme, according to the study. When looking at tissue samples from patients with colorectal cancer, but no prior history of ulcerative colitis, they found similar changes in protein levels.

Researchers were aware that naturally occurring gut bacteria can sometimes cause local inflammation, so they hypothesized that it may contribute to retinoic acid deficiency and colorectal cancer. To test their hypothesis, researchers used broad-spectrum antibiotics to deplete the bacteria in mice.

The results of the experiment showed that tumor formation dramatically decreased in multiple cancer models, and prevented the alteration in retinoic acid metabolism.

“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. “Normally retinoic acid levels are regulated extremely tightly. This discovery could have important implications for the treatment of human colorectal cancer.”

Upon further investigation, the results showed that retinoic acid is able to block or slow the development of cancer by activating a CD8 T cell, which kill off cancer cells, according to the study.

In mouse models, lower levels of retinoic acid resulted in reduced numbers and activation of CD8 T cells in the intestinal tissue, while also increasing their tumor burden.

“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.”