Oncotarget

Research Papers:

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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Oncotarget. 2016; 7:23919-23932. https://doi.org/10.18632/oncotarget.8081

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Abstract

Zsuzsanna Nemeth1,4, Eva Csizmadia1, Lisa Vikstrom1, Mailin Li1, Kavita Bisht1,5, Alborz Feizi1, Sherrie Otterbein6, Brian Zuckerbraun6, Daniel B. Costa2,3, Pier Paolo Pandolfi2,3, Janos Fillinger7, Balazs Döme4,8,9, Leo E. Otterbein1, Barbara Wegiel1,2

1Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

2Cancer Center Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

3Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

4Department of Tumor Biology, National Koranyi Institute of TB and Pulmonology, Budapest, Hungary

5Heart Foundation Research Center, Griffith Health Institute, Griffith University, Gold Coast, Australia

6Department of Surgery, Section of Trauma and Acute Care Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

7Department of Pathology, National Koranyi Institute of TB and Pulmonology, Budapest, Hungary

8Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria

9Department of Thoracic Surgery, National Institute of Oncology, Budapest, Hungary

Correspondence to:

Barbara Wegiel, e-mail: bwegiel@bidmc.harvard.edu

Keywords: tumor microenvironment, carbon monoxide, macrophages, immunotherapy

Received: December 08, 2015    Accepted: February 29, 2016    Published: March 15, 2016

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.


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