**2. TLRs genetics and regulation of signaling**

TLRs were first described in Drosophila in 1984, and were later discovered in vertebrates including humans [1, 3]. Till date, 13 TLRs are discovered in mammals, and 10 are functional in humans [2]. Genes encoding human TLRs are located on chromosomes 1 (TLR5), 3 (TLR9), 4 (TLR1, TLR2, TLR3, TLR6 and TLR10), 9 (TLR4) and X (TLR7 and TLR8) [1, 5]. TLR1–9 is conserved in both human and mice; however, mouse TLR10 is not functional because of a retrovirus insertion, and TLR11–13 has been lost from the human genome [8, 19, 20].

A number of genetic changes like single nucleotide polymorphisms (SNPs) within the TLR genes has been reported in humans which can influence receptor binding and function, that ultimately influences the risk for the inflammatory diseases as well as cancers [21]. Although there have been numerous studies reporting the impact of polymorphisms on TLR function and disease development, there is still a lot of contradiction in terms of outcomes [22].

#### *Role of Toll-Like Receptor (TLR)-Signaling in Cancer Progression and Treatment DOI: http://dx.doi.org/10.5772/intechopen.94423*

A recent report has shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in cancer biology. Overwhelming evidence supports that TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response for further growth and migration [23]. The TLR family can be largely divided into 2 subgroups, extracellular and intracellular, depending on their cellular localization. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11 are located on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are localized to the endosomal/ lysosomal compartment [10]. The subcellular localization of TLR4 is unique because it is localized to both plasma membrane as well as endosomal vesicles [24]. TLRs are type I transmembrane proteins that consist of three major domains: (1) a leucine rich extracellular domain, (2) a transmembrane domain, (3) A cytoplasmic TIR (Toll/Interleukin-1 Receptor) domain. The recognition of ligand by TLRs is mediated by the extracellular domain that harbor a leucine rich repeat (LRR) composed of 19–25 tandem copies of the "xLxxLxLxx" motif [25]. TLR signaling was extensively studied in the recent years. There are two important TLR pathways: one is dependent on myeloid differentiation factor 88 (MYD88) adaptor proteins and the other is independent of MYD88.

All TLRs except TLR3, which exclusively uses the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway, use MYD88 as the downstream adapter protein that activate the classical/canonical inflammatory signaling pathway [26–29]. After activation with their specific ligands, TLRs recruit MYD88, leading to subsequent activation of three main transcription factors: interferonregulatory factors (IRF3, IRF5 and IRF7), NF-kB, MAPK and AP1 [21–25, 27–32]. Subsequently, it promote the transcription of cytokines such as TNF-α, IL-6 and IL-1, chemokines and interferons which are key mediators of inflammation [30].

#### **Figure 1.**

*Toll-like receptors (TLRs) signaling pathway:Toll-like receptors (TLRs) recognize different ligands and triggered innate immune responses. The activation of the TLR signaling pathway originates from the cytoplasmic TIR domain that associates with an adaptor, MYD88. IRAK is activated by phosphorylation and associates with TRAF6, leading to activation NF-*κ*B. Activation of MYD88- independent pathways occurs via TRIF and TRAF activates interferon--regulatory factor (IRF). Then they promote the transcription of inflammation mediators: Cytokines, chemokines and interferons.*

Expression of cytokines also leads to maturation of dendritic cells and activation of B-cells and T-cells, which underlies the involvement of TLR in adaptive immunity [23]. TLR2 and TLR4 upon binding with their respective ligands form dimeric complexes, followed by recruitment of 5 specific adapters, including 1) MYD88, 2) TIR domain containing adaptor protein (TIRAP)/MYD88 adaptor like (Mal), 3) TRIF, 4) TRIF-related adaptor molecule (TRAM), and 5) sterile α and armadillo motifcontaining protein (SARM) [19, 33]. This response elicits the downstream responses like proliferation, invasion, inflammation and tumorigenesis etc. The schematic representation of the role of various TLRs signaling pathways is shown in **Figure 1**. This alternative/non-canonical pathway culminates in the activation of TRAF3 and interferon regulatory factor 3 (IRF3), which results in the secretion of type I IFNs, which are required for an effective antiviral response [31].
