title: Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth.
abstract: 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.
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Department of Tumor Biology, National Koranyi Institute of TB and Pulmonology, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Nemeth
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Vikstrom
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Mailin
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Heart Foundation Research Center, Griffith Health Institute, Griffith University, Gold Coast, Australia.
authors.forename: Kavita
authors.initials: K
authors.lastname: Bisht
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Alborz
authors.initials: A
authors.lastname: Feizi
authors.affiliation: Department of Surgery, Section of Trauma and Acute Care Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Sherrie
authors.initials: S
authors.lastname: Otterbein
authors.affiliation: Department of Surgery, Section of Trauma and Acute Care Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Zuckerbraun
authors.affiliation: Cancer Center Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.affiliation: Cancer Center Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Department of Pathology, National Koranyi Institute of TB and Pulmonology, Budapest, Hungary.
authors.forename: Janos
authors.initials: J
authors.lastname: Fillinger
authors.affiliation: Department of Tumor Biology, National Koranyi Institute of TB and Pulmonology, Budapest, Hungary.|Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.|Department of Thoracic Surgery, National Institute of Oncology, Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Döme
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Cancer Center Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wegiel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051940:B7-2 Antigen / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002248:Carbon Monoxide / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051940:B7-2 Antigen; D014408:Biomarkers, Tumor; C497964:CD86 protein, human; D017382:Reactive Oxygen Species; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases
keywords: carbon monoxide; immunotherapy; macrophages; tumor microenvironment