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

Paula A. Bousquet, Sebastian Meltzer, Linda Sønstevold, Ying Esbensen, Svein Dueland, Kjersti Flatmark, Beathe Sitter, Tone Frost Bathen, Therese Seierstad, Kathrine Røe Redalen, Lars Eide, Anne Hansen Ree

Research output: Contribution to journalArticle

Abstract

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% O2) or hypoxia (0.2% O2) 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.

LanguageEnglish (US)
Pages76-83
Number of pages8
JournalTranslational Oncology
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Rectal Neoplasms
Mitochondrial DNA
Reactive Oxygen Species
Inflammation
DNA Damage
Neoplasms
Serum
Colorectal Neoplasms
Cell Line
Neoadjuvant Therapy
Interleukin-1 Receptors
Carcinoembryonic Antigen
Choline
Tumor Hypoxia
C-Reactive Protein
Disease-Free Survival
Therapeutics
Tumor Necrosis Factor-alpha
Prospective Studies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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.

In: Translational Oncology, Vol. 12, No. 1, 01.01.2019, p. 76-83.

Research output: Contribution to journalArticle

Bousquet, PA, Meltzer, S, Sønstevold, L, Esbensen, Y, Dueland, S, Flatmark, K, Sitter, B, Bathen, TF, Seierstad, T, Redalen, KR, Eide, L & Ree, AH 2019, 'Markers of Mitochondrial Metabolism in Tumor Hypoxia, Systemic Inflammation, and Adverse Outcome of Rectal Cancer' Translational Oncology, vol. 12, no. 1, pp. 76-83. https://doi.org/10.1016/j.tranon.2018.09.010
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. In: Translational Oncology. 2019 ; Vol. 12, No. 1. pp. 76-83.
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