Influence of High-Fat Diet on Colorectal Cancer

Poor diet is associated with 80 percent of colorectal cancer cases, but the exact pathways by which diet leads to cancer are not known.

In a newly published study, Cleveland Clinic researchers have identified a specific molecular pathway that plays a key role in the link between a high-fat diet and tumor growth in the colon.

In the July 6 issue of Stem Cell Reports, the team showed that colon cancer stem cell growth in mice was enhanced by a high-fat, Western diet. Cancer stem cells are a subset of resilient, aggressive malignant cells that are believed to be partially responsible for spread and recurrence of cancer.

The researchers focused on the JAK2-STAT3 cellular signaling pathway, a widely studied pathway known to promote tumor growth. When the JAK2-STAT3 pathway was blocked, the spike in cancer stem cell growth caused by the high-fat diet declined, providing more insight into how this pathway is linked to diet-related cancer. Researchers anticipate that pinpointing the exact mechanism can lead to the development of therapeutics to counteract the negative effects of a Western diet on colorectal cancer.

Colorectal cancer is the third most common cancer in the United States with more than 130,000 cases reported annually. The disease arises as a result of a combination of several genetic, epigenetic and environmental causes, such as diet.

“We have known the influence of diet on colorectal cancer. However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway,” said Matthew Kalady, MD, co-author of the study, colorectal surgeon, and co-director of the Cleveland Clinic Comprehensive Colorectal Cancer Program.  “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.”

The team analyzed human colorectal cancer-free survival data in the Cancer Genome Atlas and evaluated primary and metastasized colorectal cancer specimens via microarray analysis. They further verified the link between high-fat diet and stem cell maintenance in obesity-resistant mice.

“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,” said Justin D. Lathia, Ph.D., associate professor in the Lerner Research Institute’s Department of Cellular and Molecular Medicine and co-author of the study.

Senior author of the study was the late Noa Noy, PhD, and first author was Sheelarani Karunanithi, PhD. The laboratories of Drs. Ofer Reizes, PhD, Justin D. Lathia, PhD, and Matthew Kalady, MD, participated in the study.