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Du et al. TLRs in cancer

TLRs can stimulate autophagy, which conversely metabolism leads to metabolic disorders and local
regulates TLRs and their signal transduction, with hypoxia, through which large amounts of tissue cell
the mechanism unknown. We recently reported that debris and proteins are released. The debris and
microtubule-associated protein 1S (MAP1S), an proteins are recognized by TLRs as DAMPs, which
intracellular autophagy-related molecule, can regulate are considered signals of danger, and this recognition
TLRs and their signaling. MAP1S plays an important consequently influences the various biological
[44]
role in cell cycle arrest induced by the flagellin/TLR5 behaviors of tumor cells. It has been reported that
signaling pathway in human breast cancer cell MCF-7, HMGB1, an endogenous ligand of TLR2 which binds
and it is also involved in the inhibition of cell migration to TLR2 and activates TLR2 signaling pathways in
of MCF-7 by flagellin. To sum up, given the increasing glioblastoma, mediates antitumor immune response
evidence of mutuality between TLRs and tumors, by inducing the activation of DCs and their migration
more attention has been given to innate immunity in into the brain tumor. [54]
tumor cells, especially regarding TLRs expression and
signaling pathway, both of which play a significant role TLR signaling promotes tumor growth
in the development of cancer. The activation of TLRs can also promote tumor growth
in many situations. Recent studies have found that the
TLRs PLAY A CRITICAL ROLE IN TUMOR combination of highly expressed TLRs and DAMPs
DEVELOPMENT in tumors changes the homeostasis of the immune
system, which leads to the suppression of immune
TLR signaling inhibits tumor growth function. HMGB1 has been identified as a cause of
The TLRs play an immune surveillance role mainly by tumors of the skin, liver and pancreas. Furthermore,
inducing the production of multiple cytokines and the TLR4 recognizes and combines with HMGB1 released
activation of immune cells. Cytokines such as type I by necrotic cells, and this recognition may eventually
interferon (IFN-I) and interleukin 12 (IL-12) promote cause immune tolerance by activating the downstream
the activation of NK cells and enhance the scavenging pro-inflammatory signaling pathway. At the same
capacity of the host with tumor cells. Other cytokines time, HMGB1 aggregates in the cell membrane and
[45]
such as IL-2 and IFN-γ can enhance the ability of promotes the invasion and growth of tumor cells. [23]
tumor-specific cytotoxic T lymphocyte (CTL) in the host
to recognize and scavenge tumor cells. Intriguingly, Although the specific mechanisms of TLR-mediated
some TLRs agonists were found capable of inhibiting immune escape are still unknown, the high expression
tumor growth. [46-49] It has been reported that the of TLRs in tumors often leads to immunosuppression
combination of TLR agonists, chemotherapy drugs and while enhancing the invasiveness of tumors. Studies
tumor vaccine could improve the efficacy of eliminating have found that the activation of the TLRs signaling
tumor cells, an effect mainly based on the activation pathway may lead to increased secretion of IL-10 and
of antigen-presenting cells and the enhancement of TGF-β, both of which are major immune suppressors
T-cell immune response by TLRs. The increased in vivo. In addition, the activation of TLRs is also
[50]
[55]
expression of MHCII, CD88 and CCR7 in the activated accompanied by the expression of PD-L1, HLA-G and
antigen presenting cells of the TLRs signaling pathway [56]
significantly enhances recognition and presenting to other inhibitory costimulatory molecules. In a mouse
tumor antigen. Also, TLR1/2 acting on CD8 CTLs model of colon cancer, TLR4 has prolonged the survival
+
increases the secretion of IFN-γ, TNF-α and IL-2 to time of tumor cells by up-regulating programmed death
promote the secretion of granzyme B and perforin by ligand 1 (PD-L1/B7-H1), inducible costimulator ligand
CD8 T cells, which play a key role in elimination of (B7-H2) and down-regulating the expression level of
+
[57]
tumor cells. [51] Fos. Supernatants generated from murine colon
cancer cells stimulated with LPS were found to play a
In addition, TLRs also act directly on tumor cells; significant role in the inhibition of T cell proliferation and
TLR3 is thought to be effective in promoting tumor NK cell cytotoxicity. The effect can be reversed after
cell apoptosis in a variety of tumors. When activated the TLR4 signaling pathway is blocked, which may
[58]
by dsRNA, an agonist of TLR3, breast cancer cells explain the pathway’s immunosuppressive effect.
generate autocrine type I IFN, which mediates TLR3 In addition to the inhibiting role, TLRs also promote
dependent cell apoptosis. [52,53] In type I and II lung the proliferation of tumor cells and enhances tumor
cancer cells, the engagement of TLR3 by dsRNA invasion, promoting immune escape, while TLR2
induces an atypical caspase-8-containing complex, in human gastric cancer cell lines promotes tumor
which activates apoptotic pathways leading to tumor progression through the induction of COX-2, PGE-2
cell death. In the development of tumors, vigorous and IL-8. [57]
[53]
466 Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 29, 2016