Multiple roles of toll-like receptor 4 in colorectal cancer

Abstract

Toll-like receptor (TLR) signaling has been implicated in the inflammatory responses in intestinal epithelial cells (IECs). Such inflammatory signals mediate complex interactions between commensal bacteria and TLRs and are required for IEC proliferation, immune response, repair, and homeostasis. The upregulation of certain TLRs in colorectal cancer (CRC) tissues suggests that TLRs may play an essential role in the prognosis of chronic and inflammatory diseases that ultimately culminate in CRC. Here, we provide a comprehensive review of the literature on the involvement of the TLR pathway in the initiation, progression, and metastasis of CRC, as well as inherited genetic variation and epigenetic regulation. The differential expression of TLRs in epithelial cells has also been discussed. In particular, we emphasize the physiological role of TLR4 in CRC development and pathogenesis, and propose novel and promising approaches for CRC therapeutics with the aid of TLR ligands.

Keywords: colorectal cancer; immune response; inflammation; ligand; toll-like receptor 4.

Figure 1

The TLR4 signaling pathway. TLR4 is activated by LPS, whereas CD14 and MD2 act as accessory proteins for LPS/TLR4 binding. Upon ligand binding, TLR4 dimerizes, and recruits downstream adaptor molecules such as MyD88/MAL and TRIF/TRAM to mount an inflammatory response. The activated MyD88/MAL then activates IRAK4, TRAF6, TAK1, and IKK complexes, while TRIF/TRAM signals through RIP1 to TRAF6/TAK1 and IKK. After this, both these pathways converge at NF-κB. The cytoplasmic NF-κB complex is maintained in the inactive state by IκB, which is in turn degraded by proteasomes, resulting in the translocation of NF-κB into the nucleus. Besides activating NF-κB, TAK1 also phosphorylates MAPKs to further reinforce the inflammatory response. The TRIF/TRAM pathway not only activates NF-κB but also triggers IRF3 to mount an antiviral response. Cumulatively, all these signaling pathways assist in eradicating infection as well as play an important role in sustaining the normal physiological functions in IECs.

Figure 2

Homeostatic interaction between microbiota and TLRs. TLRs play an important role in maintaining normal functions of IECs; however, regulation of the activation and induction of TLRs through various mechanisms is necessary for this role. TLRs in the intestine exist in close proximity to and may be stimulated by commensal bacteria. Therefore, it is extremely necessary to regulate their functions. Under normal conditions, homeostasis between bacterial induction and TLR activation is maintained to ensure a disease-free status. On the other hand, if TLRs are inappropriately activated or if they mount an exaggerated immune response to a low level stimulus, they may culminate in bacterial infection and inflammatory disease/cancer, respectively.