Prospective Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2017; 23(26): 4831-4838
Published online Jul 14, 2017. doi: 10.3748/wjg.v23.i26.4831
Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer
Karoliina Paarnio, Sara Väyrynen, Kai Klintrup, Pasi Ohtonen, Markus J Mäkinen, Jyrki Mäkelä, Tuomo J Karttunen
Karoliina Paarnio, Sara Väyrynen, Kai Klintrup, Pasi Ohtonen, Markus J Mäkinen, Jyrki Mäkelä, Tuomo J Karttunen, Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029 Oulu, Finland
Karoliina Paarnio, Kai Klintrup, Pasi Ohtonen, Jyrki Mäkelä, Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, POB 5000, 90014 Oulu, Finland
Sara Väyrynen, Markus J Mäkinen, Tuomo J Karttunen, Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014 Oulu, Finland
Author contributions: Mäkelä J and Karttunen TJ contributed equally to this work; Paarnio K, Mäkelä J and Karttunen TJ designed the research; Paarnio K and Väyrynen S analyzed the tissue samples; Klintrup K recruited the patients and organized the collection of the tissue samples; Ohtonen P and Paarnio K analyzed the data; Paarnio K, Mäkinen MJ, Karttunen TJ and Mäkelä J wrote the paper.
Supported by a grant from the Mary and Georg C Ehrnrooth Foundation, Finland.
Institutional review board statement: The study was reviewed and approved by the Regional Ethical Committee of North Ostrobothnia Hospital District (58/2005, 184/2009, 60/2012).
Informed consent statement: All study participants provided informed written consent prior to study enrolment. The data is stored and handled anonymously.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Karoliina Paarnio, MD, Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, POB 5000, 90014 Oulu, Finland.
Telephone: +358-40-0764976 Fax: +358-08-3155318
Received: December 14, 2016
Peer-review started: December 16, 2016
First decision: February 23, 2017
Revised: March 14, 2017
Accepted: May 19, 2017
Article in press: May 19, 2017
Published online: July 14, 2017

To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa.


We analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed.


Normal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours.


Tumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.

Keywords: Colorectal Cancer, Toll-like receptor 2, Toll-like receptor 4, Inflammation, Prognosis

Core tip: Toll-like receptor 4 (TLR4) is downregulated in colorectal cancer (CRC), suggesting a role as a tumour suppressor. Low expression of TLR4 in the invasive front marks poor prognosis and is associated with metastatic disease. The most significant finding was the association between weak TLR4 expression in the tumour front and 36.9% (P = 0.044) lower cancer-specific survival in cancer of the proximal colon as compared with strong TLR4 expression. Weak TLR4 staining in tumour front was present in 50% (11/22) of the cases with metastases and only in 17% (16/94) of those without metastases (P = 0.001). TLR2 is upregulated in CRC but not associated with prognosis.