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Du et al. TLRs in cancer

RNA (dsRNA) which constitutes the genome of decreases in the size, incidence and number of
[16]
RNA viruses; TLR4 is well known as a sensor of chemical-induced liver cancer neoplasms, indicating
lipopolysaccharide (LPS) from bacteria; TLR5 is an important contribution of TLR signaling to hepato-
[17]
responsible for the recognition of flagellin; single- carcinogenesis. [33,34] Two TLRs, TLR5 and TLR9, are
[18]
stranded RNA is identified as the ligands of TLR7 and considered to be associated with cervical cancer;
TLR8; and intracellular TLR9 senses unmethylated the expression of these two receptors increases
[19]
CpG oligonucleotide (ODN). The specific ligand for significantly in higher grades of cervical cancer while
[20]
TLR10 has not yet been defined. TLR11 in mouse this expression is rarely detected in normal cervical
macrophages is known to recognize uropathogenic squamous epithelial cells. The expression of TLR9
[35]
Escherichia coli, but TLR11 is not expressed in promotes angiogenesis and is associated with lower
humans. [21] lung cancer survival rates. Moreover, TLR9 promotes
[36]
the proliferation of prostate cancer cells in time- and
Signaling for TLR is initiated by recognition of dose-dependent manners confirmed by the expression
PAMPs and the ligand-induced dimerization of TLRs level of NF-kB and downstream c-Myc. [37]
[Figure 1]. Upon activation, TLRs recruit TIR-domain-
containing adaptor proteins for the subsequent Although many TLRs promote the occurrence and
activation of downstream signaling. The adaptors development of tumors via a variety of mechanisms,
include myeloid differentiation factor-88 (MyD88), Toll/ some TLRs might have an antitumor effect. Therefore,
IL-1 receptor domain adaptor protein, TIR-domain- the activation of TLRs in cancer cells can play a
containing adapter-inducing interferon-β (TRIF), complex role. The upregulation of TLR1 and TLR2 in
TRIF-related adaptor molecule and sterile-α and bladder cancer promotes the nuclear translocation
armadillo motif-containing protein. These adaptors of NF-kB and the activation of the c-JNK signaling
provide receptor sites for relevant proteins and initiate pathway, which increases the secretion of IL-1, IL-6
various signaling events, which results in a variety of and IL-8.
inflammatory cytokines transcription by mediating the
phosphorylation of IkBα to active NF-kB. The multiple Moreover, TLR3 is considered to promote the death
signaling pathways contribute to the rapid response of tumor cells in various cancers. A study by Paone et al.
[38]
of the innate immune system to the pathogens. In indicated that the TLR3 agonist poly I:C inhibits the
[22]
addition, the recognition of PAMPs by TLRs gives proliferation, and promotes the apoptosis, of prostate
rise to the activation and maturation of dendritic cells, cancer cells by activating protein kinases. The
and pro-inflammatory cytokines and chemokines are combination of poly I:C and 5-fluorouracil (5-FU) or
produced to induce the proliferation and differentiation IFN-α effectively induced apoptosis in human colon
of Th1 and Th2, which establishes and regulates cancer cells. Increased expression of TLR3 in human
[39]
adaptive immunity. melanoma can inhibit the proliferation and induce the
death of tumor cells with pretreatment of type I IFN.
[40]
TLRS ARE ALSO EXPRESSED IN TUMOR In addition, our study showed that the TLR5- activated
CELLS signaling pathway in breast cancer inhibits the
proliferation of tumor cells by down-regulating cyclin
[41]
The TLRs, a family of receptors in the innate immune B1, cyclin D1 and cyclin E2. In human head and neck
system, are expressed and activated in innate immune cancers, TLR5 activated by flagellin also reduces tumor
cells such as macrophages and dendritic cells. In recent cell proliferation and promotes tumor cell apoptosis.
years, however, some studies have shown that TLRs When treated with CpG oligodeoxynucleotides (CpG
are also highly expressed in various tumor cells. [23-27] ODN) 107 and irradiation, the TLR9 signaling pathway
For example, over-expression of TLR2, TLR3 and in human glioma arrests the cell cycle and reduces the
TLR4 has been detected in majority of colonic cancer proliferation of tumor cells by activating downstream
cells, [28,29] and TLR2, TLR3, TLR4 and TLR5 are highly NF-kB and NO pathways. A TLR9 agonist inhibits
[42]
expressed in ovarian cancer cells. [30,31] proliferation and promotes caspase-dependent
apoptosis of neuroblastoma cells. In addition, it has
Therefore, the study of TLR expression and function shown antitumor and anti-angiogenesis effects in renal
in cancer has become a focus for researchers. In cell carcinoma. [43]
the colon mucosa of polyposis patients, high mRNA
copy numbers of TLR3 have been observed, and The regulation of TLRs and their signal transduction
strong TLR3 expression has been demonstrated and is complicated, and understanding of the mechanism
associated with colorectal cancer stages. Mice is limited. Recently, the role of autophagy in immune
[32]
deficient in TLR4 and MyD88 have shown significant response has drawn special attention because
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 29, 2016 465