Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 5, 2014
Publication Date: October 1, 2014
Citation: Yan, L., Combs, G.F. 2014. Consumption of a high-fat diet abrogates inhibitory effects of methylseleninic acid on spontaneous metastasis of Lewis lung carcinoma in mice. Carcinogenesis. 35(10):2308-2313. Interpretive Summary: Selenium is an essential nutrient with demonstrated capabilities of preventing secondary cancer. Obesity is the leading risk factor, second only to smoking, for many types of cancer, and cancer patients who are overweight or obese are at a greater risk of developing secondary cancer with shorter disease-free survival rate compared to patients with normal body weight. We investigated the anti-metastatic effect of selenium in mice fed a high-fat diet using a spontaneous metastasis model. We found that feeding mice a high-fat diet increased the spread of cancer cells from the primary tumor to the lungs, a target organ of metastasis. Feeding mice a selenium-supplemented low-fat diet reduced lung metastasis, but such an inhibition was not observed in mice fed the selenium-supplemented high-fat diet. We found that selenium reduced plasma concentrations of proteases (enzymes responsible for cancer invasion) and angiogenic factors (proteins responsible for vascular formation during tumorigenesis) regardless of the diet. We found that high-fat feeding increased plasma levels of fat cell-derived adipokines (proteins responsible for cancer invasion and angiogenesis) regardless of selenium supplementation; however, supplemental selenium reduced such adipokines in low-fat fed mice. Our results demonstrate that consumption of a high-fat diet abrogated the anti-metastatic effects of selenium, and that such an abrogation may involve fat-cell derived inflammatory cytokines. Considering the prevalence of overweight/obesity in the U.S., this finding may have relevance to achieving the best outcomes of cancer prevention, including that involving selenium.
Technical Abstract: We investigated the effect of dietary supplementation with selenium (Se) on spontaneous metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice fed a high-fat diet. Mice were fed the AIN93G diet or that diet modified with 45% calories from fat supplemented with or without 2.5 mg Se/4029 kCal as methylseleninic acid for 6 weeks, at which time they were injected subcutaneously with 2.5 x 105 LLC cells. The resulting primary tumor was removed surgically 10 days later, and the experiment was terminated after an additional 10 days. Results showed that feeding the high-fat diet was associated with a 17% increase in pulmonary metastases compared to feeding the AIN93G diet (p < 0.01). Selenium supplementation reduced the metastases by 11% compared to the non-supplemented controls (p < 0.05); however, the reduction was greater in AIN93G-fed mice (18%) than in mice fed the high-fat diet (5%). Supplemental Se reduced plasma concentrations of proteolytic proteases (urokinase plasminogen activator, p < 0.01; matrix metalloproteinase-9, p < 0.05) and angiogenic factors (vascular endothelial growth factor, p < 0.01; tissue inhibitor of metalloproteinase-1, p < 0.01) compared to non-supplemented controls. Mice fed the high-fat diet showed significantly increased plasma concentrations of adipokines plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-a, and leptin regardless of the level of dietary Se; however, supplemental Se reduced plasma PAI-1 (p = 0.05) and MCP-1 (p = 0.05) in AIN93G-fed mice. These results demonstrate that consumption of a high-fat diet abrogated the anti-metastatic effects of Se, and that such an abrogation may involve adipose-derived inflammatory cytokines.