The Role of PGE2 in Colorectal Cancer Metastasis

Researchers seek drug targets superior to nonsteroidal anti-inflammatory drugs.

For the first time, scientists at Arizona State University have identified the details of how inflammation triggers colon cancer cells to metastasize. The findings will allow researchers to develop new drugs that specifically target the prevention and treatment of colon cancer.

“We’ve long known that simple things like taking aspirin or other anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs, or NSAIDs), have beneficial effects on reducing the risk of colorectal cancer,” said lead researcher Raymond DuBois, MD, PhD. “But non-aspirin NSAIDs can cause serious cardiovascular side effects when taken over a long period of time, so we’ve needed to discover better drug targets. This study points us in the right direction.”

The study’s findings could lead scientists to develop more effective treatment options for patients affected by colon cancer. Currently, nearly half of patients with advanced colorectal cancer die within five years following treatment.

This may be in part due to the fact that the cancer becomes more chemotherapy resistant, but other evidence supports the role of inflammation and inflammatory mediators in tumor growth and spread.

The study showed how a colon cancer could essentially “outsmart” its host by using an inflammatory mediator to expand its cancer stem cells in order to metastasize. Researchers showed a direct link between the pro-inflammatory mediator prostaglandin E2 and increased colorectal cancer stem cells.

Cancer stem cells (CSCs) are said to be responsible for tumor initiation, growth, relapse, and recurrence. Cancer is largely made up of CSCs as well as other types of rapidly dividing cells.

Prostaglandin E2 is the most abundant pro-inflammatory bioactive fat, or lipid, found in colon, lung, breast, head, and neck cancers. High levels of PGE2 indicate a poor outcome for individuals suffering from cancer diagnoses.

“The normal role of PGE2 is to come to the rescue when you do something like cut your finger,” Dr. DuBois said. “It attracts the body’s immune cells and stimulates pathways that heal the wound site. The level of PGE2 goes up and then goes down within a few days of healing the wound. But in cancer, the cells keep making PGE2 chronically, so it’s like this wounding process that never heals. In doing so, it generates these cancer stem cells that promote cancer progression and metastatic spread.”

The team of researchers discovered that when PGE2 binds to the receptor on the surface of the cancer cell EP4, it triggers the signal for cancer stem cells to renew, differentiate, and eventually become resistant to chemotherapy. In this way, the cancer tumor cells trick the body into producing more PGE2 to aid in the renewal process of cancer stem cells.

This concept was proven in DuBois’ mouse model of colorectal cancer where higher levels of PGE2 were associated with an increase in the number of CSCs and overall tumor burden. In this model, the liver was one of the prime organ targets for colorectal cancer to first spread.

“We use a combination of approaches that utilize human tissues and mouse models to complete our studies,” Dr. DuBois said. “We take samples from human colon cancers and then purify the cancer stem cell population. When we treat these stem cells with PGE2, we found that they are 1000 times more metastatic than the cells we don’t treat with PGE2.”

The same could be observed in human samples of colorectal cancer.

Furthermore, when they were able to block the PGE2 signaling by adding a drug that inhibits binding to the EP4 receptor, it reduced the number of polyps and CSCs and blocked liver metastasis.

With this new study completed and the findings indicating the importance of the role of PGE2 in cancer tumor metastasis, Dr. DuBois is hopeful about future cancer treatments. Human clinical trials are still needed to test the safety and efficacy of the new drug targeting technique.

“Now, if we can just target and eliminate the stem cells from people with colon cancer, we can develop a new therapeutic approach to treat colorectal cancer and improve outcomes,” Dr. DuBois said.