Author
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Yan, Lin |
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Demars, Lana |
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Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 9/30/2014 Publication Date: 10/30/2014 Citation: Yan, L., Demars, L.C. 2014. Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice. PLoS One. 9(10):e110869. Interpretive Summary: Obesity is a leading risk factor for cancer, second only to smoking. Being obese/overweight at the time of diagnosis of primary cancer is associated with poor prognosis and greater risk of developing recurrent cancer, which directly affects the quality life and survival of cancer patients. Adipose tissue is an endocrine organ that produces many inflammatory cytokines that are not only responsible for obesity but also function as tumor promoters. Plasminogen activator inhibitor-1 (PAI-1) is such an inflammatory cytokine. In the present study, we investigated the effects of deletion of PAI-1 gene from on cancer spread to the lungs in mice fed a low-fat diet (15% calories from fat) and a high-fat diet (45% calories from fat). We found that consumption of the high-fat diet increased the number and size of tumors developed in the lungs and such increases were accompanied with increases in adipose and plasma concentrations of PAI-1. Depletion of PAI-1 significantly reduced the number and size of tumors formed in the lungs. Furthermore, we found significant increases in plasma levels of other cancer promoting inflammatory cytokines and angiogenic factors in PAI-1 deficient mice, which may support cancer progression in the absence of PAI-1. We concluded that PAI-1 participated in cancer metastasis and depletion of PAI-1 reduced high-fat enhanced metastasis. Plasminogen activator inhibitor-1 is a potential therapeutic target in cancer treatment. Our results suggest the possibility that treatments targeting on PAI-1, particularly those aimed at long-term inhibition, may be counteracted by the compensatory overproduction of inflammatory cytokines and angiogenic factors. This warrants further investigations, particularly in clinical studies on PAI-1 and cancer prevention and treatment. Technical Abstract: We investigated the effects of plasminogen activator inhibitor-1 (PAI-1) deficiency on spontaneous metastasis of Lewis lung carcinoma (LLC) in PAI-1 deficient (PAI-1-/-) and wildtype mice (C57BL/6J background) fed the AIN93G diet or that diet modified with 45% calories from fat. The high-fat diet increased the number of pulmonary metastases by 60% (p < 0.01), tumor cross-sectional area by 82% (p < 0.05) and tumor volume by 130% (p < 0.05) compared to the AIN93G diet. Deficiency of PAI-1 reduced the number of metastases by 35% (p < 0.01) compared to wildtype mice. In mice fed the high-fat diet, PIA-1 deficiency reduced tumor cross-sectional area by 52% (p < 0.05) and tumor volume by 61% (p < 0.05) compared to their wildtype counterparts; but PAI-1 deficiency had no significant effects on mice fed the AIN93G diet. Adipose and plasma concentrations of PAI-1 were significantly higher in high-fat fed wildtype mice than in their AIN93G-fed counterparts; they were not detectable in PAI-1-/- mice regardless of the diet. Conditioned medium from LLC cells was found to contain 32.7 ng PAI-1/mg protein. Furthermore, PAI-1 deficient mice showed significantly greater plasma concentrations of monocyte chemotactic protein-1, tumor necrosis factor-a, leptin, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1 and insulin compared to wildtype mice. Those findings suggest that PAI-1 produced by the host promotes high-fat enhanced LLC progression and that compensatory overproduction of inflammatory cytokines and angiogenic factors may support LLC progression in the absence of PAI-1. |
