Submitted to: Oncotarget
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/12/2016
Publication Date: 8/25/2016
Citation: Sundaram, S., Yan, L. 2016. Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice. Oncotarget. 7:65669-65675. doi:10.18632/oncotarget.11598.
Interpretive Summary: Obesity is a leading risk factor for cancer. Being obese at the time of diagnosis of primary cancer is associated with poor prognosis and greater risk of developing recurrent or metastatic cancer, which directly affects the quality life and survival of cancer patients. Weight reduction through energy restriction is considered useful in alleviating obesity and obesity-associated cancer risk. We studied the effects of energy restriction on cancer metastasis, the most devastating aspect of cancer, in a mouse model of lung metastasis. Restricting the intake of a high-fat diet by 5% significantly reduced body fat mass but maintained the growth similar to mice fed a low-fat diet. Restricted compared to unrestricted feeding of the high-fat diet reduced the number and size of cancer nodules formed in lungs and reduced blood concentrations of proinflammatory cytokines and angiogenic factors that are associated with body fat mass buildup. Inhibition of metastasis by the restricted feeding is likely through its action on reducing body fat mass and downregulating its associated production of cancer promoting proinflammatory cytokines and angiogenic factors. This study suggests that dietary energy restriction, by reducing body adiposity and maintaining a healthy body weight, may reduce the risk of recurrence and metastasis in cancer survivors after treatment of primary cancer, and thus improve prognosis and quality of life.
Technical Abstract: Obesity is a risk factor for cancer. The objective of this study was to determine the effects of dietary energy restriction on high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC) in mice. Male C57BL/6 mice were fed an AIN93G diet or a high-fat diet (16% or 45% of energy from corn oil) or a high-fat diet with a 5% restriction of the intake. Restricted compared to unrestricted feeding of the high-fat diet reduced body adiposity and body weight, but maintained growth similar to mice fed the AIN93G diet. Compared to the AIN93G diet, the high-fat diet significantly increased the number and size (cross-sectional area and volume) of metastases formed in lungs. Restricted feeding reduced the number of metastases by 23%, metastatic cross-sectional area by 32% and volume by 45% compared to the high-fat diet. The high-fat diet elevated plasma concentrations of proinflammatory cytokines (monocyte chemotactic protein-1, plasminogen activator inhibitor-1, leptin), angiogenic factors (vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1) and insulin. The restricted feeding significantly reduced the high-fat diet-induced elevations in plasma concentrations of proinflammatory cytokines, angiogenic factors and insulin. These results demonstrated that restricting diet intake by 5% reduced high-fat diet-enhanced metastasis. The anti-metastatic effects of energy restriction may be associated with the mitigation of adiposity and down-regulation of cancer promoting proinflammatory cytokines and angiogenic factors.