Adipose-specific monocyte chemotactic protein-1 deficiency reduces pulmonary metastasis of Lewis lung carcinoma in mice

Authors: Yan, Lin; Sundaram, Sneha

Submitted to: Anticancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2019
Publication Date: 4/1/2019
Citation: Yan, L., Sundaram, S. 2019. Adipose-specific monocyte chemotactic protein-1 deficiency reduces pulmonary metastasis of Lewis lung carcinoma in mice. Anticancer Research. https://doi.org/10.21873/anticanres.13279.
DOI: https://doi.org/10.21873/anticanres.13279

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 cancer spread, 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 fat tissue-produced 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 spread to the lungs. Deficiency of MCP-1 in fat tissue (by knocking down the gene 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 spread. 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: Monocyte chemotactic protein-1 (MCP-1) is a potent adipokine. This study tested the hypothesis that adipose-produced MCP-1 contributes to metastasis. In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male adipose MCP-1 deficient (MCP-1-/-) and wild-type (WT) mice were fed a control AIN93G diet or a high-fat diet (HFD) containing 16% or 45% of energy from soybean oil for 11 weeks. Lung metastasis from a primary tumor, established by subcutaneous injection of LLC cells, was the primary endpoint. There was no difference in the percent fat body mass between MCP-1-/- and WT mice fed the same diet nor differences in energy intake among the four groups. The adipose expression of MCP-1 mRNA and protein was lower in MCP-1-/- mice than in WT controls. The HFD increased the number of metastases formed in the lungs in WT mice. The number of metastasis was significantly lower in MCP-1-/- mice fed the HFD than in WT mice fed the HFD but was higher than WT mice fed the AIN93G diet. The volume of metastases was smaller in MCP-1-/- mice than in WT mice, regardless of diet. When compared to that in WT mice, adipose MCP-1 deficiency lowered concentrations of insulin, proinflammatory adipokines (leptin, plasminogen activator inhibitor-1, and resistin), and angiogenic markers (vascular endothelial growth factor, hepatic growth factor, and angiopoietin-2) in plasma. These findings indicate that adipose MCP-1 knockdown may down-regulate inflammation and angiogenesis during malignant aggression. We conclude that adipose MCP-1 deficiency attenuates HFD-enhanced pulmonary metastasis of LLC, which supports the hypothesis that adipose-produced MCP-1 contributes to malignant spread.