Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth

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

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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.

Original languageEnglish
Pages (from-to)23919-32
Number of pages14
JournalOncotarget
Volume7
Issue number17
DOIs
Publication statusPublished - 15 Mar 2016
Externally publishedYes

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Tumor Microenvironment
Carbon Monoxide
Lung Neoplasms
Mitogen-Activated Protein Kinase 1
Growth
Heme Oxygenase-1
Macrophages
Gases
Neoplasms
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
Heterografts
Reactive Oxygen Species
Apoptosis
Phenotype
Lung
Enzymes

Keywords

  • Journal Article

Cite this

Nemeth, Z., Csizmadia, E., Vikstrom, L., Li, M., Bisht, K., Feizi, A., ... Wegiel, B. (2016). Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth. Oncotarget, 7(17), 23919-32. https://doi.org/10.18632/oncotarget.8081
Nemeth, Zsuzsanna ; Csizmadia, Eva ; Vikstrom, Lisa ; Li, Mailin ; Bisht, Kavita ; Feizi, Alborz ; Otterbein, Sherrie ; Zuckerbraun, Brian ; Costa, Daniel B ; Pandolfi, Pier Paolo ; Fillinger, Janos ; Döme, Balazs ; Otterbein, Leo E ; Wegiel, Barbara. / Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth. In: Oncotarget. 2016 ; Vol. 7, No. 17. pp. 23919-32.
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Nemeth, Z, Csizmadia, E, Vikstrom, L, Li, M, Bisht, K, Feizi, A, Otterbein, S, Zuckerbraun, B, Costa, DB, Pandolfi, PP, Fillinger, J, Döme, B, Otterbein, LE & Wegiel, B 2016, 'Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth', Oncotarget, vol. 7, no. 17, pp. 23919-32. https://doi.org/10.18632/oncotarget.8081

Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth. / Nemeth, Zsuzsanna; Csizmadia, Eva; Vikstrom, Lisa; Li, Mailin; Bisht, Kavita; Feizi, Alborz; Otterbein, Sherrie; Zuckerbraun, Brian; Costa, Daniel B; Pandolfi, Pier Paolo; Fillinger, Janos; Döme, Balazs; Otterbein, Leo E; Wegiel, Barbara.

In: Oncotarget, Vol. 7, No. 17, 15.03.2016, p. 23919-32.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth

AU - Nemeth, Zsuzsanna

AU - Csizmadia, Eva

AU - Vikstrom, Lisa

AU - Li, Mailin

AU - Bisht, Kavita

AU - Feizi, Alborz

AU - Otterbein, Sherrie

AU - Zuckerbraun, Brian

AU - Costa, Daniel B

AU - Pandolfi, Pier Paolo

AU - Fillinger, Janos

AU - Döme, Balazs

AU - Otterbein, Leo E

AU - Wegiel, Barbara

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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.

AB - 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.

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DO - 10.18632/oncotarget.8081

M3 - Article

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VL - 7

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JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 17

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Nemeth Z, Csizmadia E, Vikstrom L, Li M, Bisht K, Feizi A et al. Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth. Oncotarget. 2016 Mar 15;7(17):23919-32. https://doi.org/10.18632/oncotarget.8081