Submitted to: Oncotarget
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/28/2016
Publication Date: 4/26/2016
Citation: Yan, L., Sundaram, S. 2016. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. Oncotarget. 7(17):24792-24799.
Interpretive Summary: Obesity is a leading risk factor for cancer, second only to smoking. Being obese at the time of diagnosis of primary cancer is positively associated with poor prognosis and a greater risk of developing recurrent cancer, aspects that directly affect the quality life and survival of cancer patients. Fat tissue produces many chemicals called adipokines that are increased by obesity. Monocyte chemotactic protein-1 (MCP-1) is such an adipokine. In the present study, we studied the effects of MCP-1 on cancer spread to the lungs from a subcutaneous primary tumor in mice fed a high-fat diet. We found that consumption of the high-fat diet increased the number and size of tumors developed in lungs and such increases were accompanied with increases in concentrations of MCP-1 in fat tissue and blood. Depletion of MCP-1 from mice (by knocking out genes responsible for producing MCP-1) significantly reduced the number and size of tumors formed in the lungs, particularly in mice fed the high-fat diet. This indicates that MCP-1 produced by fat tissue contributes, at least partly, to high-fat diet-enhanced cancer development and growth. We suggest that reduction in MCP-1, through prevention of obesity, may attenuate cancer progression particularly in those patients who are obese or overweight.
Technical Abstract: Obesity is a risk factor for cancer. Adipose tissue produces pro-inflammatory adipokines that contribute obesity-related malignant progression. This study investigated the effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice fed a high-fat diet (45% of energy from fat). The high-fat diet significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet (16% of energy from fat). Deficiency of MCP-1 significantly reduced lung metastases by 37% in high-fat diet-fed mice; it significantly reduced metastatic cross-sectional area by 46% and volume by 69% compared to wild-type mice. Adipose and plasma concentrations of MCP-1 were significantly higher in high-fat diet-fed wild-type mice than in their AIN93G-fed counterparts, and they were not detectable in MCP-1 deficient mice regardless of diet. Plasma concentrations of plasminogen activator inhibitor-1, tumor necrosis factor-a, vascular endothelial growth factor and tissue inhibitor of metalloproteinase-1 were significantly higher in MCP-1 deficient mice compared to wild-type mice. We conclude that adipose-produced MCP-1 contributes to high-fat diet-enhanced metastasis. While knockout of MCP-1 reduced metastasis, the elevated production of inflammatory cytokines and angiogenic factors in the absence of MCP-1 may support the metastatic development and growth of LLC in MCP-1 deficient mice.