Abstract
Adipose-produced pro-inflammatory cytokines contribute to obesity and cancer. This 2×2 experiment was designed to investigate effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in MCP-1 deficient and wild-type mice fed a modified AIN93G diet containing 16% and 45% of energy from corn oil, respectively. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet. Deficiency in MCP-1 reduced lung metastases by 37% in high-fat diet-fed mice; it 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; they were not detectable in MCP-1 deficient mice regardless of diet. Plasma concentrations of plasminogen activator inhibitor-1, tumor necrosis factor-α, 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 MCP-1 deficiency reduces metastasis, the elevation of pro-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.
Highlights
Monocyte chemotactic protein-1 (MCP-1) is a member of the chemokine family composed of 76 amino acids, and it is 13 kDa in size [1]
In our studies on the roles of diet in metastasis using the spontaneous metastasis model of Lewis lung carcinoma (LLC), we found that high-fat diet enhances metastasis, which is accompanied by increases in plasma concentrations of adipokines including MCP-1 [20, 21]
Results from the present study are consistent with previous reports that feeding mice an obesogenic, Figure 3: The number a. cross-sectional area b. and volume c. of pulmonary metastases in MCP-1-/- and wild-type mice fed the AIN93G or the high-fat diet
Summary
Monocyte chemotactic protein-1 (MCP-1) is a member of the chemokine family composed of 76 amino acids, and it is 13 kDa in size [1]. Studies in recent years reveal that functions of MCP-1 are far beyond tissue repair; it participates in pathophysiological development of various diseases including cancer and obesity. High expression of MCP1 is positively associated with advanced pathologic stages of prostate cancer [3] and with multiple liver metastases of colorectal cancer [5]. In breast cancer, it is a significant indicator of early relapse [4]. Animal studies indicate that MCP-1 participates in primary tumor growth and metastasis [6,7,8]. Treatment of mice with a neutralizing antibody to MCP-1 reduces the growth and metastasis of non-small-cell lung carcinoma [6]; stable knockdown of MCP-1 in MDA-MB-231 mammary carcinoma cells reduces their metastasis in vivo [7]
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