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Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()()

Tumor hypoxia contributes to therapy resistance and metastatic progression of locally advanced rectal cancer (LARC). We postulated that the tumor mitochondrial metabolism, manifested by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage, reflects how hypoxic conditions connect to can...

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Autores principales: Bousquet, Paula A., Meltzer, Sebastian, Sønstevold, Linda, Esbensen, Ying, Dueland, Svein, Flatmark, Kjersti, Sitter, Beathe, Bathen, Tone Frost, Seierstad, Therese, Redalen, Kathrine Røe, Eide, Lars, Ree, Anne Hansen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170256/
https://www.ncbi.nlm.nih.gov/pubmed/30273860
http://dx.doi.org/10.1016/j.tranon.2018.09.010
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author Bousquet, Paula A.
Meltzer, Sebastian
Sønstevold, Linda
Esbensen, Ying
Dueland, Svein
Flatmark, Kjersti
Sitter, Beathe
Bathen, Tone Frost
Seierstad, Therese
Redalen, Kathrine Røe
Eide, Lars
Ree, Anne Hansen
author_facet Bousquet, Paula A.
Meltzer, Sebastian
Sønstevold, Linda
Esbensen, Ying
Dueland, Svein
Flatmark, Kjersti
Sitter, Beathe
Bathen, Tone Frost
Seierstad, Therese
Redalen, Kathrine Røe
Eide, Lars
Ree, Anne Hansen
author_sort Bousquet, Paula A.
collection PubMed
description Tumor hypoxia contributes to therapy resistance and metastatic progression of locally advanced rectal cancer (LARC). We postulated that the tumor mitochondrial metabolism, manifested by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage, reflects how hypoxic conditions connect to cancer-induced systemic inflammation and poor outcome. Levels of ROS and mtDNA damage were analyzed in three colorectal cancer (CRC) cell lines cultured for 24 hours under normoxia (21% O(2)) or hypoxia (0.2% O(2)) and serum sampled at the time of diagnosis from 35 LARC patients participating in a prospective therapy study. Compared with normoxia, ROS were significantly repressed and mtDNA damage was significantly enhanced in the hypoxic CRC cell lines; hence, a low ratio of ROS to mtDNA damage was an indicator of hypoxic conditions. In the LARC patients, low serum ROS were associated with elevated levels of circulating carcinoembryonic antigen and tumor choline concentration, both indicative of unfavorable biology, as well as adverse progression-free and overall survival. A low ratio of ROS to mtDNA damage in serum was associated with poor local tumor response to the neoadjuvant treatment and, of note, elevated systemic inflammation factors (C-reactive protein, the interleukin-1 receptor antagonist, and factors involved in tumor necrosis factor signaling), indicating that deficient treatment response locally and detrimental inflammation systemically link to a hypoxic mitochondrial metabolism. In conclusion, serum ROS and damaged mtDNA may be markers of the mitochondrial metabolism driven by the state of oxygenation of the primary tumor and possibly implicated in systemic inflammation and adverse outcome of LARC.
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spelling pubmed-61702562018-10-10 Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()() Bousquet, Paula A. Meltzer, Sebastian Sønstevold, Linda Esbensen, Ying Dueland, Svein Flatmark, Kjersti Sitter, Beathe Bathen, Tone Frost Seierstad, Therese Redalen, Kathrine Røe Eide, Lars Ree, Anne Hansen Transl Oncol Original article Tumor hypoxia contributes to therapy resistance and metastatic progression of locally advanced rectal cancer (LARC). We postulated that the tumor mitochondrial metabolism, manifested by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage, reflects how hypoxic conditions connect to cancer-induced systemic inflammation and poor outcome. Levels of ROS and mtDNA damage were analyzed in three colorectal cancer (CRC) cell lines cultured for 24 hours under normoxia (21% O(2)) or hypoxia (0.2% O(2)) and serum sampled at the time of diagnosis from 35 LARC patients participating in a prospective therapy study. Compared with normoxia, ROS were significantly repressed and mtDNA damage was significantly enhanced in the hypoxic CRC cell lines; hence, a low ratio of ROS to mtDNA damage was an indicator of hypoxic conditions. In the LARC patients, low serum ROS were associated with elevated levels of circulating carcinoembryonic antigen and tumor choline concentration, both indicative of unfavorable biology, as well as adverse progression-free and overall survival. A low ratio of ROS to mtDNA damage in serum was associated with poor local tumor response to the neoadjuvant treatment and, of note, elevated systemic inflammation factors (C-reactive protein, the interleukin-1 receptor antagonist, and factors involved in tumor necrosis factor signaling), indicating that deficient treatment response locally and detrimental inflammation systemically link to a hypoxic mitochondrial metabolism. In conclusion, serum ROS and damaged mtDNA may be markers of the mitochondrial metabolism driven by the state of oxygenation of the primary tumor and possibly implicated in systemic inflammation and adverse outcome of LARC. Neoplasia Press 2018-09-29 /pmc/articles/PMC6170256/ /pubmed/30273860 http://dx.doi.org/10.1016/j.tranon.2018.09.010 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Bousquet, Paula A.
Meltzer, Sebastian
Sønstevold, Linda
Esbensen, Ying
Dueland, Svein
Flatmark, Kjersti
Sitter, Beathe
Bathen, Tone Frost
Seierstad, Therese
Redalen, Kathrine Røe
Eide, Lars
Ree, Anne Hansen
Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()()
title Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()()
title_full Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()()
title_fullStr Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()()
title_full_unstemmed Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()()
title_short Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer()()
title_sort markers of mitochondrial metabolism in tumor hypoxia, systemic inflammation, and adverse outcome of rectal cancer()()
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170256/
https://www.ncbi.nlm.nih.gov/pubmed/30273860
http://dx.doi.org/10.1016/j.tranon.2018.09.010
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