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World J Gastroenterol. Dec 21, 2014; 20(47): 17699-17708
Published online Dec 21, 2014. doi: 10.3748/wjg.v20.i47.17699
Toll-like receptor signaling in colorectal cancer: Carcinogenesis to cancer therapy
Ting-Ting Li, Shuji Ogino, Zhi Rong Qian
Ting-Ting Li, Department of Geriatric Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
Ting-Ting Li, Shuji Ogino, Zhi Rong Qian, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, United States
Shuji Ogino, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, United States
Shuji Ogino, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02215, United States
Author contributions: Li TT and Qian ZR contributed equally to this paper; Li TT and Qian ZR did problem formulation; Li TT performed literature search and wrote the paper; Qian ZR and Ogino S revised the manuscript.
Supported by grant from United States National Institute of Health (NIH), No. P01 CA87969 (to SE Hankinson), No. UM1 CA167552, and No. P01 CA55075 (to WC Willett), No. R01 CA137178 (to AT Chan), No. P50 CA127003 (to CS Fuchs), No. R01 CA151993 (to S Ogino); Bennett Family Fund for Targeted Therapies Research; and Entertainment Industry Foundation through National Colorectal Cancer Research Alliance
Correspondence to: Zhi Rong Qian, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room M420, Boston, MA 02215, United States. zhirong_qian@dfci.harvard.edu
Telephone: +1-617-5829145 Fax: +1-617-5828558
Received: May 28, 2014
Revised: August 27, 2014
Accepted: November 18, 2014
Published online: December 21, 2014
Processing time: 206 Days and 9.2 Hours
Abstract

Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.

Keywords: Toll-like receptor; Colorectal cancer; Carcinogenesis; Prognosis; Cancer therapy

Core tip: Toll-like receptors (TLRs) are innate immune sensors which can recognize inflammatory mediators. TLRs have been shown to mediate inflammatory response and maintain epithelial barrier homeostasis. Inflammation is a risk factor for many cancers including colorectal cancer (CRC). The key molecules involved in inflammation-driven carcinogenesis include TLRs. In this paper, we reviewed TLR signaling in CRC from carcinogenesis to cancer therapy.