Diet, inflammation, and cancer linked through certain lipids

A category of lipids known as sphingolipids may be an important link in the relationship between diet, inflammation, and cancer. The sphingolipid metabolite known as sphingosine-1-phosphate (S1P) was found to contribute to inflammation of the colon, inflammatory bowel disease (IBD), and inflammation-associated colon cancer. Further, soy and plant-type sphingolipids may protect against these conditions. S1P is found in both mammalian food products and generated by normal human cells.

A connection between inflammation and cancer has been recognized for more than a hundred years. This connection is particularly evident in colon carcinogenesis, because patients with IBD have a higher incidence of colon cancer than the general population.

Bioactive sphingolipids play fundamental roles in carcinogenesis. They have the ability to regulate programmed cell death pathways, stress responses, immunity, and inflammation. In colon cancer, gut epithelial cells are exposed to sphingolipid metabolites generated by the breakdown of dietary sphingolipids.

The final breakdown product of mammalian sphingolipids is S1P, and it is a pro-inflammatory signaling lipid that promotes cell growth and carcinogenesis. During malignant transformation and colon cancer progression, genetic changes occur in the gut tissues, including an increase in the enzyme that generates S1P and a decrease in S1P lyase (SPL), the enzyme that breaks down S1P. These changes lead to accumulation of S1P in the gut mucosa.

To explore the impact of S1P accumulation on inflammation and carcinogenesis, a research team led by Julie Saba, MD, PhD of the Children's Hospital Oakland Research Institute (CHORI) in California produced a mouse lacking SPL in the gut tissues. They then characterized its responses using a chemical-induced model of colitis-associated colon cancer.

Compared to control mice, the mutated mice exhibited more inflammation and a higher incidence of tumors on this regimen. Using a combination of mouse and cell culture experiments, the scientists identified a cascade of steps downstream of S1P that lead eventually to the silencing of two tumor suppressing proteins whose functions are to protect against the formation of cancer. Their findings were published in The Journal of Clinical Investigation (2014; doi:10.1172/JCI74188).

In contrast to the cancer-promoting effects of S1P, the researchers showed that soy or plant-type sphingolipids, called sphingadienes, cannot be metabolized to S1P and instead enhance the metabolism of S1P by increasing SPL levels in gut tissues when fed to mice. Further, sphingadiene treatment of mice reduced inflammation, signs of IBD, and the incidence of tumors. Finally, the researchers showed an increase in S1P-related gene expression in the colons of patients with IBD compared to controls.

The research suggests that while mammalian sphingolipids may promote inflammation and carcinogenesis, plant/soy sphingolipids cannot be converted into S1P, are anti-inflammatory, and reduce the activity of several cancer signaling pathways.

The data suggests that dietary sphingolipids may enhance or inhibit colon carcinogenesis, depending on their ability to be metabolized to S1P. The findings reveal a mechanistic link between diet, inflammation, and cancer and provide evidence supporting the further investigation of sphingadienes as colon cancer chemopreventive agents in patients at risk, such as children and adults with IBD.

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