Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis

PLoS One. 2011;6(12):e28133. doi: 10.1371/journal.pone.0028133. Epub 2011 Dec 1.


Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits growth of cancer cells including non-small cell lung cancer (NSCLC). Clinically, use of thiazolidinediones, which are pharmacological activators of PPARγ is associated with a lower risk of developing lung cancer. However, the role of this pathway in lung cancer metastasis has not been examined well. The systemic effect of pioglitazone was examined in two models of lung cancer metastasis in immune-competent mice. In an orthotopic model, murine lung cancer cells implanted into the lungs of syngeneic mice metastasized to the liver and brain. As a second model, cancer cells injected subcutaneously metastasized to the lung. In both models systemic administration of pioglitazone increased the rate of metastasis. Examination of tissues from the orthotopic model demonstrated increased numbers of arginase I-positive macrophages in tumors from pioglitazone-treated animals. In co-culture experiments of cancer cells with bone marrow-derived macrophages, pioglitazone promoted arginase I expression in macrophages and this was dependent on the expression of PPARγ in the macrophages. To assess the contribution of PPARγ in macrophages to cancer progression, experiments were performed in bone marrow-transplanted animals receiving bone marrow from Lys-M-Cre+/PPARγ(flox/flox) mice, in which PPARγ is deleted specifically in myeloid cells (PPARγ-Mac(neg)), or control PPARγ(flox/flox) mice. In both models, mice receiving PPARγ-Mac(neg) bone marrow had a marked decrease in secondary tumors which was not significantly altered by treatment with pioglitazone. This was associated with decreased numbers of arginase I-positive cells in the lung. These data support a model in which activation of PPARγ may have opposing effects on tumor progression, with anti-tumorigenic effects on cancer cells, but pro-tumorigenic effects on cells of the microenvironment, specifically myeloid cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary*
  • Animals
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Coculture Techniques
  • Disease Progression
  • Fluorescent Antibody Technique
  • Green Fluorescent Proteins / genetics*
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology*
  • PPAR gamma / agonists
  • PPAR gamma / physiology*
  • Pioglitazone
  • Rosiglitazone
  • Thiazolidinediones / administration & dosage


  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • enhanced green fluorescent protein
  • Rosiglitazone
  • Green Fluorescent Proteins
  • Pioglitazone