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. 2014 Oct 30;9(10):e110869. doi: 10.1371/journal.pone.0110869. eCollection 2014.

Abstract

This study investigated the effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma (LLC) in plasminogen activator inhibitor-1 deficient (PAI-1-/-) and wild-type mice. 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 in PAI-1 reduced the number of metastases by 35% (p<0.01) compared to wild-type mice. In mice fed the high-fat diet, PAI-1 deficiency reduced tumor cross-sectional area by 52% (p<0.05) and tumor volume by 61% (p<0.05) compared to their wild-type counterparts; however, PAI-1 deficiency affected neither area nor volume in mice fed the AIN93G diet. Adipose and plasma concentrations of PAI-1 were significantly higher in high-fat fed wild-type mice than in their AIN93G-fed counterparts. Adipose and plasma PAI-1 were not detectable in PAI-1-/- mice regardless of the diet. Mice deficient in PAI-1 showed significantly greater plasma concentrations of monocyte chemotactic protein-1, tumor necrosis factor-α, leptin, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1 and insulin compared to wild-type mice, indicating a compensatory overproduction of inflammatory cytokines, angiogenic factors and insulin in the absence of PAI-1. We conclude that PAI-1 produced by the host, including that by adipose tissue, promotes high-fat enhanced metastasis of LLC.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Lewis Lung / blood*
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology
  • Cytokines / blood
  • Cytokines / genetics
  • Dietary Fats / pharmacology*
  • Lung Neoplasms / blood*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neoplasm Proteins / blood*
  • Neoplasm Proteins / genetics
  • Serpin E2 / blood*
  • Serpin E2 / genetics

Substances

  • Cytokines
  • Dietary Fats
  • Neoplasm Proteins
  • Serpin E2
  • Serpine2 protein, mouse

Grant support

Funding for this work was provided by the U.S. Department of Agriculture, ARS, Research project 5450-51000-045-00D. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.