A
team of Children’s Hospital and Research Center Oakland (CHORI) researchers has
found that a category of lipids known as sphingolipids may be an important link
in the relationship between diet, inflammation and cancer. In a paper
published online this week in the Journal of Clinical Investigation, Dr. Julie
Saba, MD, PhD and her team provide evidence that a sphingolipid metabolite
called sphingosine-1-phosphate (S1P) found in both mammalian food products and
generated by normal human cells can contribute to inflammation of the colon,
inflammatory bowel disease (IBD) and inflammation-associated colon cancer,
whereas soy and plant-type sphingolipids called sphingadienes may protect
against these conditions.
A
connection between inflammation and cancer has been recognized for over 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. There is increasing evidence that inflammation contributes
to the earliest stages of carcinogenesis, namely in the process of cell
transformation, where the cell acquires many aspects of cancer characteristics.
The observation that IBD and colon cancer incidence rise as nations
industrialize suggests that changes in diet and nutrition contribute to colitis
and colitis-associated colon cancer.
Bioactive
sphingolipids play fundamental roles in carcinogenesis via their ability to
regulate programmed cell death pathways, stress responses, immunity, and
inflammation. The impact of sphingolipid metabolism is particularly germane in
colon cancer, as gut epithelial cells are exposed to sphingolipid metabolites
generated by the breakdown of dietary sphingolipids. S1P, the final breakdown
product of mammalian sphingolipids, 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 catalyzes S1P degradation. These changes lead to accumulation
of S1P in the gut mucosa.
To
explore the impact of S1P accumulation on inflammation and carcinogenesis, the
researchers 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.
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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