US research showed in pre-clinical models that cancer stem cell growth in the colon was enhanced by a high-fat, Western diet.
Poor diet is associated with 80% 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 tumour growth in the colon.
The team showed in pre-clinical models that cancer stem cell growth in the colon 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. Furthermore, when the researchers blocked the JAK2-STAT3 cellular signalling pathway, a widely studied pathway known to promote tumour growth, the spike in cancer stem cell growth caused by the high-fat diet declined.
This study provides more insight into how the JAK2-STAT3 pathway is linked to diet-related cancer. Pinpointing the exact mechanism can help researchers develop therapeutics to counteract the negative effects of a Western diet on colorectal cancer.
Colorectal cancer is the third most common cancer in the US 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 Dr Matthew Kalady, co-author of the study, colorectal surgeon, and co-director of the Cleveland Clinic Comprehensive Colorectal Cancer Programme. “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 analysed human colorectal cancer-free survival data in the Cancer Genome Atlas and evaluated primary and metastasised 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 Dr Justin D Lathia.
The transmembrane protein, STRA6, functions as a vitamin A transporter and a cytokine receptor when activated by vitamin A-bound serum retinol binding protein 4 (RBP4). STRA6 activation transduces a JAK2-STAT3 signaling cascade and promotes tumorigenesis in a xenograft mouse model of colon cancer. We show here that RBP4 and STRA6 expression is associated with poor oncologic prognosis. Downregulating STRA6 or RBP4 in colon cancer cells decreased the fraction of cancer stem cells and their sphere and tumor initiation frequency. Furthermore, we show that high-fat diet (HFD) increases LGR5 expression and promotes tumor growth in a xenograft model independent of obesity. HFD increased STRA6 levels, and downregulation of STRA6 delays and impairs tumor initiation, tumor growth, and expression of stemness markers. Together, these data demonstrate a key role of STRA6 and RBP4 in the maintenance of colon cancer self-renewal and that this pathway is an important link through which consumption of HFD contributes to colon carcinogenesis.
Sheelarani Karunanithi, Liraz Levi, Jennifer DeVecchio, George Karagkounis, Ofer Reizes, Justin D Lathia, Matthew F Kalady, Noa Noy