**4. Molecular mechanism of TLRs in cancer progression**

Overall, as discussed earlier, the activation of TLRs can promote as well as inhibit tumor growth and cancer progression, but the actual underlying molecular mechanism still remains elusive. TLRs are also involved in controlling many important cellular processes like cell proliferation, survival, apoptosis, cell migration, metastasis and angiogenesis [16]. TLR signaling has been implicated in various autoimmune, chronic inflammation and inflammatory diseases. This situation creates a microenvironment that is rich in growth and survival factors, which leads to the development of various types of cancer [41]. High TLR expression has been reported in several cancer types including cancerous cell lines. It was known that TLR4 and TLR5 are over expressed in gastric epithelium infected with *H. pylori* as well as in precursor lesions [37, 42]. It is considered that TLRs enable cells to interact with *H. pylori* which can induce the expression of tumorigenic factors and may promote cancer development. TLR over–expression has also been found in colon cancer, hepatocellular carcinoma, ovarian and cervical cancers, breast and prostate cancers, lung cancer, melanoma and neuroblastoma [43]. TLR expression in cancer cells has been linked with cancer progression, evasion of immune surveillance, apoptosis and survival. Recent studies have shown high expression of TLR4 in lung cancer cells, which is linked with expression of immunosuppressive cytokines (TGFb), angiogenic factors VEGF and IL-8, and increased resistance to apoptosis [16, 42]. Cell proliferation and production of pro-inflammatory cytokines IL-6 and IL-8 can be significantly decreased by silencing of TLR4 expression in breast cancer cell line (MDA-MB-231) [44]. Other studies in ovarian cancer and cell lines has shown that TLR4 and NF-kB activation by LPS and paclitaxel respectively promotes production of IL-8, IL-6, VEGF and MCP-1 while TLR4 silencing lead to loss of resistance to Paclitaxel [45]. TLR2 mRNA expression was significantly higher in sporadic colorectal cancer cells than in noncancerous cells [45]. On the basis of above mentioned facts, we can deduce that various TLRs might trigger different signaling pathways in cancer initiation and progression [46].

A recent report found that activation of TLRs may induce cancerous cells to secrete a number of soluble factors, which play distinct roles in cancer development. The role of TLRs in cancer progression needs to be further investigated, and in depth precise underlying mechanism must be elucidated for further development of TLR agonists as therapeutic agents.
