Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth

• DOI: 10.18632/oncotarget.8081
• Publication Date: 2016-03-15T06:45:36Z
• Authors: Zsuzsanna Nemeth; Eva Csizmadia; Lisa Vikstrom; Mailin Li; Kavita Bisht; Alborz Feizi; Sherrie Otterbein; Brian Zuckerbraun; Daniel B. Costa; Pier Paolo Pandolfi; Janos Fillinger; Balazs Döme; Leo E. Otterbein; Barbara Wegiel
• Keywords: 0301 basic medicine; Lung Neoplasms; Oncology and carcinogenesis not elsewhere classified; 610; Apoptosis; p38 Mitogen-Activated Protein Kinases; carbon monoxide; Mice; 03 medical and health sciences; Journal Article; Biomarkers, Tumor; Tumor Microenvironment; tumor microenvironment; Animals; Humans; Carbon monoxide; Cells, Cultured; Cell Proliferation; Mitogen-Activated Protein Kinase 1; Carbon Monoxide; Mitogen-Activated Protein Kinase 3; Macrophages; Oncology and carcinogenesis; macrophages; 3. Good health; Mice, Inbred C57BL; Tumor microenvironment; 2730 Oncology; immunotherapy; Immunotherapy; B7-2 Antigen; Reactive Oxygen Species; Heme Oxygenase-1; Research Paper; Signal Transduction

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.