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The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018
Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth
Zsuzsanna Nemeth1,2, Eva Csizmadia1, Lisa Vikstrom1
1Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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.
Insights
Carbon monoxide (CO) controls tumor-associated macrophages (TAMs), reprogramming them to an anti-tumoral phenotype. This mechanism involves reactive oxygen species (ROS) and the MAPK/Erk1/2 pathway, impacting lung cancer progression.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Tumor-associated macrophages (TAMs) play a crucial role in tumor progression.
- The role of diffusible gases in modulating TAMs remains incompletely understood.
Purpose of the Study:
- To investigate the role of carbon monoxide (CO) in controlling TAMs and their anti-tumoral effects.
- To elucidate the molecular mechanisms underlying CO-mediated TAM reprogramming in lung cancer.
Main Methods:
- Treatment of lung tumors with low doses of CO.
- Analysis of CD86 expression and MAPK/Erk1/2 pathway activation in the tumor microenvironment.
- Assessment of CO's anti-tumoral effects in A549 xenografts.
- Investigation of ROS-dependent and Notch 1-dependent pathways.
- Correlation analysis in human lung cancer specimens.
Main Results:
- Low-dose CO induces apoptosis in lung tumors, correlating with increased CD86 expression and MAPK/Erk1/2 activation.
- CD86-positive cells are essential for CO's anti-tumoral effects.
- CO reprograms macrophages via ROS-dependent MAPK/Erk1/2-c-myc and Notch 1-dependent HO-1 pathways.
- A negative correlation between HO-1 and active MAPK-Erk1/2 was observed in human lung cancer.
Conclusions:
- CO acts as a non-cell autonomous regulator of the tumor microenvironment by modulating macrophages.
- The study reveals novel mechanisms involving ROS, MAPK/Erk1/2, and Notch 1 pathways in CO-mediated anti-tumoral effects.
- Findings suggest CO as a potential therapeutic agent for lung cancer through immune modulation.
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