Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth

Oncotarget. 2016 Apr 26;7(17):23919-32. doi: 10.18632/oncotarget.8081.


We hypothesized that tumor-associated macrophages (TAMs) are controlled by the diffusible gas carbon monoxide (CO). We demonstrate that induction of apoptosis in lung tumors treated with low doses of CO is associated with increased CD86 expression and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (Erk) 1/2 pathway in tumor microenvironment. Presence of CD86-positive cells was required for the anti-tumoral effects of CO in established A549 xenografts. We show that the effects of CO on tumor stroma and reprogramming of macrophages towards the anti-tumoral phenotype is mediated by reactive oxygen species (ROS)-dependent activation of MAPK/Erk1/2-c-myc pathway as well as Notch 1-dependent negative feedback on the metabolic enzyme heme oxygenase-1 (HO-1). We find a similar negative correlation between HO-1 and active MAPK-Erk1/2 levels in human lung cancer specimens.In summary, we describe novel non-cell autonomous mechanisms by which the diffusible gas CO dictates changes in the tumor microenvironment through the modulation of macrophages.

Keywords: carbon monoxide; immunotherapy; macrophages; tumor microenvironment.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • B7-2 Antigen / metabolism
  • Biomarkers, Tumor / metabolism*
  • Carbon Monoxide / pharmacology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Tumor Microenvironment / drug effects*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • B7-2 Antigen
  • Biomarkers, Tumor
  • CD86 protein, human
  • Reactive Oxygen Species
  • Carbon Monoxide
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases