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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2018
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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. |
format | Online Article Text |
id | pubmed-6170256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
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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