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Du et al. TLRs in cancer

INTRODUCTION are ten TLRs in humans, classified as two subgroups
based on their cellular localization: TLR 1, 2, 4, 5, 6
[8]
The discovery of Toll-like receptors (TLRs) and 10 are located on the cell surface and respond
approximately twenty years ago is a revolutionary event primarily to pathogen-associated molecular patterns
in life science and medical research, and helps improve (PAMPs) such as lipids and bacterial proteins. In
our understanding about the role of innate immunity in contrast, TLR 3, 7, 8 and 9 are located intracellularly
both the physiology and pathology of human health. in the endosomes, responding primarily to nucleic
The medical community came to realize that innate acids from both viruses and bacteria. The TLRs are
[9]
immunity is essential and critical in immune responses a class of type I transmembrane proteins comprised
to pathogen infections and in connection with the of an extracellular domain, transmembrane region
activation of adaptive immunity. [1-3] Therefore, the 2011 and intracellular domain. The ectodomain contains
[10]
Nobel Prize in Physiology or Medicine was awarded leucine-rich repeats and two to four evolutionarily
to scientists who made significant contributions to the conserved cysteine structures which recognize and
discoveries concerning TLRs and their role in innate bind to evolutionarily conserved molecular motifs in
immunity. These discoveries mean that researchers PAMPs. The intracellular domain is highly homologous
now understand TLR biology much better [Figure 1]. [4-6] among the TLRs and contains a toll/interleukin-1
In this article, we summarize the role of TLRs in the receptor (TIR) domain, which is crucial to the
immune system and focus on the expression of TLRs intracellular activation of signaling cascades leading
in cancer cells and their role in cancer progression. to the induction of pro-inflammatory cytokines and
Finally, we discuss the current status of research in chemokines. [11]
utilizing TLR agonists as potential therapeutic agents
in cancer treatment. The TLRs recognize PAMPs from micro-organisms
or danger-associated molecular patterns (DAMPs)
TLRs: THE KEY SENSORS IN INNATE from damaged tissues to activate innate and
IMMUNE RESPONSE adaptive immune responses. A variety of ligands
corresponding to distinct TLRs have been identified
The TLRs are a family of evolutionarily conserved so far [Figure 1]. [12-14] For example, TLR2 recognizes
pattern recognition receptors which play a vital role peptidoglycan and lipoteichoic acid from bacterial
[15]
in immune responses against infection. [1-3,7] There cell wall; TLR3 recognizes double-stranded

Figure 1: TLR ligands and TLR signaling pathways. Cell surface TLRs, including TLR-1, -2, -4, -5, -6, -10, and -11, and intracellular TLRs,
[70]
including TLR-3, -7, -8, and -9, recognize their specific PAMPs to activate TLR signaling cascades. TLR: Toll-like receptor; PAMPs:
pathogen associated molecular patterns
464 Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 29, 2016