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

doi:10.1016/j.tranon.2018.09.010

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

Transl Oncol. 2019 Jan;12(1):76-83. doi: 10.1016/j.tranon.2018.09.010. Epub 2018 Sep 29.

Authors

Affiliations

¹ Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway; Department of Clinical Molecular Biology, Akershus University Hospital, 1478 Lørenskog, Norway. Electronic address: Anna.Paula.Bousquet@ahus.no.
² Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway. Electronic address: sebastian.meltzer@medisin.uio.no.
³ Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway; Department of Clinical Molecular Biology, Akershus University Hospital, 1478 Lørenskog, Norway. Electronic address: Linda.Sonstevold@ife.no.
⁴ Department of Clinical Molecular Biology, Akershus University Hospital, 1478 Lørenskog, Norway. Electronic address: q.y.esbensen@medisin.uio.no.
⁵ Department of Oncology, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: svedue@ous-hf.no.
⁶ Department of Tumor Biology, Oslo University Hospital, 0424 Oslo, Norway; Department of Gastroenterological Surgery, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway. Electronic address: kjersti.flatmark@rr-research.no.
⁷ Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7491 Trondheim, Norway. Electronic address: beathe.sitter@ntnu.no.
⁸ Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7491 Trondheim, Norway. Electronic address: tone.f.bathen@ntnu.no.
⁹ Department of Radiology, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: therese.seierstad@rr-research.no.
¹⁰ Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway; Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway. Electronic address: kathrine.redalen@ntnu.no.
¹¹ Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: lars.eide@medisin.uio.no.
¹² Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway. Electronic address: a.h.ree@medisin.uio.no.

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.