University of Oulu

Päivi Sirniö, Juha P. Väyrynen, Shivaprakash J. Mutt, Karl-Heinz Herzig, Jaroslaw Walkowiak, Kai Klintrup, Jyrki Mäkelä, Tuomo J. Karttunen, Markus J. Mäkinen & Anne Tuomisto (2020) Systemic inflammation is associated with circulating cell death released keratin 18 fragments in colorectal cancer, OncoImmunology, 9:1, DOI: 10.1080/2162402X.2020.1783046

Systemic inflammation is associated with circulating cell death released keratin 18 fragments in colorectal cancer

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Author: Sirniö, Päivi1,2; Väyrynen, Juha P.1,2,3,4; Mutt, Shivaprakash J.5;
Organizations: 1Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90014, Finland
2Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu 90029, Finland
3Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
5Research Unit of Biomedicine and Biocenter Oulu, Department of Physiology, University of Oulu, Oulu 90014, Finland
6Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
7Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, POB 5000, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
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Language: English
Published: Informa, 2020
Publish Date: 2020-08-28


Systemic inflammation is a stage-independent marker of poor prognosis in colorectal cancer (CRC), activated in a complex, multifactorial process. It has been proposed that one of the main factors driving systemic inflammation may be tumor necrosis. Keratin 18 (KRT18) fragments are released from dead cells and their serum levels are markers for apoptotic and necrotic cell death. In CRC, high KRT18 levels associate with advanced disease, but their relationship with tumor necrosis and systemic inflammation is unknown. In this study, serum total soluble KRT18 (tKRT18) and apoptosis-related, caspase-cleaved fragment (aKRT18) levels were measured preoperatively from 328 CRC patients, and their difference was calculated to assess necrosis related KRT18 (nKRT18) levels. The relationships of these markers with tumor necrosis, clinicopathologic features, systemic inflammation markers (C-reactive protein, albumin, and 13 cytokines), and survival were analyzed. High serum tKRT18, aKRT18, and nKRT18 levels showed association with a higher extent of tumor necrosis, distant metastasis, and increased levels of several markers of systemic inflammation, including CXCL8. High serum tKRT18 (multivariable HR 1.94, 95% CI 1.28–2.95, p = 0.002) and nKRT18 (multivariable HR 1.87, 95% CI 1.24–2.82, p = 0.003) levels were associated with poor overall survival independent of potential confounding factors. Our results show that tumor necrosis in CRC contributes to serum levels of KRT18 fragments, and both necrosis and KRT18 levels associate with systemic inflammation. Moreover, we show that serum tKRT18 and nKRT18 levels have independent prognostic value in CRC. Our observations confirm the link between cell death and systemic inflammation.

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Series: OncoImmunology
ISSN: 2162-4011
ISSN-E: 2162-402X
ISSN-L: 2162-4011
Volume: 9
Issue: 1
Article number: 1783046
DOI: 10.1080/2162402X.2020.1783046
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by grants from Finnish Cancer Society, K. Albin Johansson Foundation, Kaarina ja Erkki Piippola Foundation.
Copyright information: © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.