Sphingolipids and colon cancer

Evidence suggests that dietary sphingolipids, acting through their hydrolysis products, ceramide and sphingosine, can inhibit the development of colon cancer (Duan, 1998 Vesper et al., 1999). In milk fat, sphingomyelin is by far the predominant sphingolipid. 

The importance of alkaline sphingomyelinase and ceramides in colon cancer is suggested by studies that compared their levels in tumors with levels in normal colonic tissue. Hertervig et al. (1997) found that the activity of alkaline sphingomyelinase was 75% less in tissue from human colon carcinomas than in normal colonic tissue. In familial adenomatous polyposis patients, there was a 90% decrease in alkaline sphingomyelinase activity in colonic adenomas and in surrounding mucosa compared to healthy controls (Hertervig et al., 1999). Human colon carcinomas had a 50% decrease in cellular ceramide content compared to normal colon mucosa (Selzner et al., 2001). 

Ceramides and sphingosine can inhibit cell growth, promote differentiation and induce apoptosis in a range of human cancer cell lines, including several types of colon cancer cells (Parodi, 2004). Selzner et al. (2001) established that ceramides induced cell death in cultured human SW403 colon cancer cells. Treatment of these cells with a ceramidase inhibitor, which prevented the catabolism of ceramides and thus increased its content in the cells, resulted in suppressed cell growth and induction of apoptosis. Selzner et al, (2001) then injected SW403 cancer cells and 

Bile acids that escape enterohepatic circulation and pass to the colon can be cytotoxic to colonocytes. Damaged cells undergo apoptosis and are shed into the lumen. To maintain cell homeostasis, new cells must be produced. This replacement can result in an increase in cell proliferation rate that can increase the risk of mutations in tumor-related genes and lead to carcinoma development. Moschetta et al. (2000) showed that sphingomyelin protected against bile acid-induced cytotoxicity in human CaCo-2 colon cancer cells, a common model for studying intestinal cell function. 

A series of studies show that sphingolipids derived from milk protect against development of colon tumors in mice. In the initial study (Dillehay et al., 1994), mice fed diets supplemented with 0.025, 0.050 or 0.1% sphingomyelin had less than half the incidence of 1,2-dimethylhydrazine (DMH)-induced colon tumors than mice fed non-supplemented diets. In addition, a diet supplemented with 0.025% of the ganglioside GMj produced significantly fewer DMH-induced aberrant crypt foci (ACF) than control animals. ACF are microscopically determined pre-neoplastic lesions that can develop into colon tumors. 

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