How does a high-fat diet raise colorectal cancer risk?

While the evidence of a link between an unhealthful diet and colorectal cancer is robust, the underlying mechanisms for this association have been unclear. A new study, however, may have uncovered an explanation.

Researchers from the Cleveland Clinic in Ohio have identified a cellular signaling pathway, called JAK2-STAT3, that drives the growth of cancer stem cells in the colon in response to a high-fat diet.

What is more, the researchers found that blocking the JAK2-STAT3 pathway in mice fed a high-fat diet halted the growth of these stem cells, a finding that might fuel the development of new drugs to treat colorectal cancer.

Study co-author Dr. Matthew Kalady, co-director of the Comprehensive Colorectal Cancer Program at the Cleveland Clinic, and colleagues recently reported their findings in the journal Stem Cell Reports.

After skin cancer, colorectal cancer - a cancer that begins in the colon or rectum - is the third most commonly diagnosed cancer in the United States.

The American Cancer Society estimate that there will be 95,520 new cases of colon cancerdiagnosed in the U.S. this year, as well as 39,910 new cases of rectal cancer.

In recent years, a wealth of studies have suggested that a high-fat diet is a risk factor for colorectal cancer. However, the precise mechanisms behind this association have been ambiguous.

With the hope of shedding light on such mechanisms, Dr. Kalady and colleagues investigated how a high-fat diet influences JAK2-STAT3, a cellular signaling pathway known to promote tumorgrowth.

Findings may fuel new treatments

To reach their findings, the researchers used microrarray analysis to assess primary and metastasized tumors in mouse models of colorectal cancer.

When the mice were fed a high-fat diet, the growth of cancer stem cells in the colon increased. Studies have indicated that cancer stem cells are a key driver in the growth and metastasis of tumors.

On further investigation, the team found that blocking the JAK2-STAT3 cellular signaling pathway in the rodents reversed the increase in cancer stem cell growth triggered by a high-fat diet.

When analyzing the effects of a high-fat diet in colorectal cancer mouse models that were obesity-resistant, the researchers were able to replicate their findings.

Dr. Kalady says that this study is the first to demonstrate how a specific molecular pathway might mediate the link between a high-fat diet and colorectal cancer, a discovery that could yield new treatments for the disease.

"We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk."

Dr. Matthew Kalady

"These findings also provide a new way in which cancer stem cells are regulated and provide insight into how environmental influences, such as diet, can alter cancer stem cell populations in advanced cancers," adds study co-author Justin D. Lathia, Ph.D., of the Lerner Research Institute at Cleveland Clinic.

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