Retinoic acid suppresses colorectal cancer development, Stanford study finds

August 30, 2016

Retinoic acid, a compound derived in the body from vitamin A, plays a critical role in suppressing colorectal cancer in mice and humans, according to researchers at the Stanford University School of Medicine.

Mice with the cancer have lower-than-normal levels of the metabolite in their gut, the researchers found. Furthermore, colorectal cancer patients whose intestinal tissues express high levels of a protein that degrades retinoic acid tend to fare more poorly than their peers.

The research is the first to unravel a complicated dance between retinoic acid levels, immune-related inflammation and gut microorganisms. It may suggest new ways to prevent or treat colorectal cancer in humans.

"The intestine is constantly bombarded by foreign organisms," said Edgar Engleman, MD, professor of pathology and of medicine. "As a result, its immune system is 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."

Engleman is the senior author of the research, which will be published online Aug. 30 in Immunity. Postdoctoral scholar Nupur Bhattacharya, PhD, and graduate student Robert Yuan share lead authorship of the study.

Tumors in mice

Retinoic acid is essential for many processes of growth and development, but it also degrades quickly when exposed to light. This makes it extremely difficult to accurately detect levels of the metabolite in the body.

The Stanford researchers collaborated with colleagues at the University of California-Berkeley, who devised a way to use a technique called quantitative mass spectrometry to measure the retinoic acid in intestinal tissues of mice treated with one or both of two chemicals: a chemical that causes intestinal inflammation, and a chemical that stimulates the development of colorectal cancer. Mice who received both chemicals develop intestinal tumors within nine to 10 weeks of treatment; those treated with just the first chemical develop intestinal inflammation but not cancers.

Engleman and his colleagues found that the mice that developed colorectal cancer had significantly lower-than-normal levels of retinoic acid in their gut than those whose intestines were inflamed but not cancerous. Further investigation showed the intestinal tissue of the animals with cancer made less of a protein that synthesizes retinoic acid and about four times more of a protein that degrades retinoic acid, leading to a rapid net decrease in levels of the metabolite.

Restoring retinoic acid levels

The researchers then tested whether it was possible to affect the disease progression by bringing the levels of retinoic acid in the tissue back into a more normal range.

"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 Engleman. "Conversely, inhibiting retinoic acid activity significantly increased the tumor burden."

The researchers next investigated the levels of the synthesis and degradation proteins in stored samples of intestinal tissue obtained from people with either ulcerative colitis or colorectal cancer associated with ulcerative colitis. Because the samples had been stored, rather than freshly collected, it was not possible to directly measure the retinoic acid levels in the human tissues.

The researchers found that, similar to what they had seen in the mice, human colorectal cancer tissue had higher levels of the degradation protein and lower levels of the synthesis protein than were found in tissue that was simply inflamed. Furthermore, they saw an inverse correlation in the amount of degradation protein and how long the patient had lived. In other words, those patients with increased amounts of the degradation enzyme in their intestinal tissue tended to fare more poorly than others with less of the enzyme.

Because the researchers also observed similar changes in protein levels in tissue samples from patients with colorectal cancer but with no prior history of ulcerative colitis, they wondered if there could be another cause of intestinal inflammation that affects retinoic acid levels. They knew that naturally occurring bacteria in the gut can sometimes cause local inflammation and hypothesized that they might contribute to the development of retinoic acid deficiency and colorectal cancer. Depleting these bacteria by treating mice with broad-spectrum antibiotics dramatically reduced tumor formation in several colorectal cancer models and prevented the alteration in retinoic acid metabolism that was seen in mice with colorectal cancer and in the human intestinal tissue.

"We found that bacteria, or molecules produced by bacteria, can cause a massive inflammatory reaction in the gut that directly affects retinoic acid metabolism," said Engleman. "Normally retinoic acid levels are regulated extremely tightly. This discovery could have important implications for the treatment of human colorectal cancer."

Further investigation showed that retinoic acid blocks or slows cancer development by activating a type of immune cell called a CD8 T cell. These T cells then kill off the cancer cells. In mice, lower levels of retinoic acid led to reduced numbers and activation of CD8 T cells in the intestinal tissue and increased the animals' tumor burden, the researchers found.

"It's become very clear through many studies that chronic, smoldering inflammation is a very important risk factor for many types of cancer," said Engleman. "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."
Other Stanford co-authors of the work are graduate student Tyler Prestwood; former clinical fellow Michael DiMaio, MD; postdoctoral scholars Nathan Reticker-Flynn, PhD, Justin Kenkel, PhD, Yaron Carmi, PhD, and Hweixian Leong Penny, PhD; clinical assistant professor of pathology Tho Pham, MD; lab manager Lorna Tolentino; research assistant Okmi Choi; and undergraduate student Reyna Hulett.

The research was supported by the National Institutes of Health (grants U01CA141468 and R01CA163441).

Stanford's Department of Pathology also supported the work.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit

Print media contact: Ruthann Richter at (650) 725-8047 (
Broadcast media contact: Margarita Gallardo at (650) 723-7897 (

Stanford University Medical Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to