Discovery of colon cancer pathway could lead to new targeted treatments

26 Feb 2019

Researchers have pinpointed a set of enzymes involved in tumour growth that could be targeted to prevent or treat colon cancer.

"We think this is a very interesting discovery," said Guodong Zhang, assistant professor of food science, whose study was published in the journal Cancer Research. "Our research identifies a novel therapeutic target and could help to develop novel strategies to reduce the risks of colon cancer."

Colon cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, according to the Centers for Disease Control and Prevention, claiming some 50,000 lives each year.

"Those statistics emphasise the need to discover new cellular targets that are crucial in the development of colon cancer", Zhang said.

In their study, UMass Amherst researchers tested their hypothesis that once present, colon cancer was increased by enzymes known as cytochrome P450 (CYP) monooxygenases and the fatty acid metabolites they form, epoxyoctadecenoic acids (EpOMEs).

The researchers compared healthy mice and mice with colon cancer by performing metabolomics - a comprehensive and complex analysis of metabolites, which are produced when food and chemicals are broken down.

In recent years, metabolomics has emerged as a powerful technology in precision medicine because it can offer a detailed picture of biological processes and molecular phenotypes, or characteristics.

Precision medicine tailors treatment to an individual's unique genetic and molecular profile.

As they suspected, the researchers found that certain fatty acid metabolites were more abundant in colon cancer.

"If a mouse has colon cancer, the plasma and colon concentrations of EpOMEs are very dramatically increased and the EpOME-producing enzymes, CYP monooxygenases, are overexpressed in the colon," Zhang explained.

Researchers also studied human colon cancer cells, comparing them to normal colon cells and found the same results: an overexpression, or plethora, of the CYP monooxygenase enzymes.

Next, using pharmacological and genetic approaches, the researchers removed or inhibited the CYP monooxygenase enzymes in mice with colon cancer and found that tumour growth was suppressed.

"If you block the enzyme, colon cancer can be significantly reduced," Zhang added.

In an effort to determine which metabolites were involved in the colon cancer-enhancing effects, researchers studied the biological actions of CYP monooxygenase metabolites.

In an in vitro test, they found that EpOME, but not other CYP monooxygenase metabolites, increased inflammation in both inflammatory and colon cancer cells.

They then treated cancer-induced mice with EpOME and found an increase in the number and size of tumours.

"We showed that at a low dose this metabolite can make colon cancer more aggressive," stated Zhang. "Taken together, the results of the research demonstrate that the previously unappreciated CYP monooxygenase pathway could be explored for preventing or treating colon cancer." 

He points out that previous studies have shown that some FDA-approved drugs inhibit CYP monooxygenases, including telmisartan, a blood pressure medication, and gemfibrozil, which is used to lower cholesterol.

"That suggests that these drugs could be repurposed for preventing or treating colon cancer," Zhang concluded. "And novel monooxygenase inhibitors could be developed for use in humans."

Using data from his groundbreaking research, Zhang has received a grant to study how dietary fats may regulate colon cancer.

EpOMEs are metabolites of linoleic acid, which are found in vegetable oils and red meat.

"Based on our findings, overconsumption of linoleic acid could increase tissue concentrations of EpOMEs, which have potent effects to exaggerate inflammation and tumour growth in the colon," Zhang concluded. "More research is needed in animal models, which can be controlled more easily than human studies. We need to better understand this pathway in colon cancer, which ultimately may help us suggest nutritional and therapeutic approaches to reduce the risks of colon cancer." 

Source: University of Massachusetts at Amherst