Should a Toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: its expression and effects in the ten most common cancers.

The expression of MD-2 in most cancer cells has not been well studied. Limited evidence has concluded that MD-2 plays a role in cancer progression only. One study highlighted that MD-2 was overexpressed in highly invasive colorectal cancer cells (SW837), in poorly differentiated, moderately invasive colorectal cancer cells (HT-29), and in well-differentiated but non-invasive colorectal cancer cells (Caco-2). 69 Another study reported that serum amyloid A 3, a major component of acute phase inflammation, binds to MD-2 and activates the MyD88-dependent TLR-4/MD-2 pathway and thus facilitates lung metastasis. 70 Therefore, MD-2 could be related to the degree of differentiation, proliferation, and migration capacity of cancers.

Prostate cancer is one of the most common causes of morbidity and mortality in men. Prostate epithelial cells are actively involved in inflammatory processes. 158 Higher levels of proinflammatory cytokines, produced through TLR-3, -4, and -9 downstream signaling pathways, were observed in the prostate tissues of cancer patients. In this study, TLR-3 -4 and -9 were highly expressed in prostate cancer tissues but not in benign tissues. Only TLR-3 levels, and not TLR-4 or TLR-9 levels, were found to have statistical significance ( P =0.016) with levels of preoperative serum prostate-specific antigen, in prostate cancer patients. 159 However, in vitro studies have shown the expression of higher levels of TLR-4 on human prostate adenocarcinoma (DU-145) cells and its activation, leading to NF-κB and proinflammatory cytokine production through the MyD88- dependent pathway. 160 Also, TLR-4 activation was found to increase the proangiogenic factor (VEGF) and immunosuppressive cytokine (TGF-β1) secretion in human prostate adenocarcinoma (PC3) cells. 161 Further, a knockdown of TLR-4 in PC3 cells resulted in the reduction of tumor cell migration and invasion. 162 These results support the negative impact of TLR-4 upregulation in prostate cancer. In addition, single nucleotide polymorphism in the TLR-4 gene is suspected to be associated with the risk of prostate carcinoma. 163 The sequence variant (11381 G/C, also known as rs11536889) in the 3′-untranslated region of the TLR-4 gene was found to be higher in patients with prostate carcinoma, in studies conducted on 1,383 Swedish patients 164 and 157 Korean patients. 165 In one study, a significantly higher risk of prostate cancer (OR: 1.26; 95% CI: 1.01–1.57) was detected among men who had a single nucleotide polymorphism of TLR-4 (GC or CC) compared with the wild-type genotype (GG). 164 However, other studies found no association of prostate cancer (OR: 1.01; 95% CI: 0.79–1.29) with this rs11536889 sequence variant of TLR-4; 166 , 167 one of these, a study involving 700 prostate cancer patients found that homozygosity of the variant alleles of these eight single-nucleotide polymorphisms of TLR-4 including rs2149356 were found to have a lower risk of prostate cancer. 166 A case-control study of 506 incident advanced prostate cancer patients found two single nucleotide polymorphisms of TLR-4 (rs10759932 and rs2149356) were associated with a higher cancer risk. 167 Nevertheless, Lindstrom et al have suggested that the association of TLR-4 with prostate cancer risk is a chance finding and that to ascertain the relationship, large sample sizes are needed. 168 The inconsistent findings of the association of genetic polymorphism of TLRs with cancer progression clearly supports the need for further investigation in this field.

The activation of TLR-4 is required for host defense against gram-negative bacteria. However, TLR-4 activation may be a double-edged sword, with both antitumor and protumor responses. The general expression of TLR-4 by all the tumor cells, suggesting TLR-4 signaling, may be continually activated and contribute to tumor initiation, progression, and also invasion. Tumor progression involves TLR-4-mediated irregular and uninhibited production of proinflammatory cytokines, chemokines, and also immunosuppressive cytokines; suggesting that the discovery of TLR-4 antagonists might be an ideal strategy to treat cancer. However, TLR-4 antagonists could pose the risk of the compromise of host immunity. Hence, it is a scientific dilemma whether a TLR-4 agonist or antagonist should be targeted for the treatment of cancer. Further studies need to be carried out to fully elucidate the effects of TLR-4 agonists and antagonists in various cancers.

Toll-like receptors (TLRs) are a recently discovered family of pattern recognition receptors that show homology with the Drosophila Toll protein and the human interleukin (IL)-1 receptor family. The first member of the TLR family to be identified was a Drosophila protein 1 implicated in dorsoventral patterning during embryonal development. TLRs are evolutionarily conserved proteins characterized by an extracellular leucine-rich repeat (LRR) domain, the transmembrane domain, and the cytoplasmic intracellular Toll/IL-1 receptor-like (TIR) domain. LRRs, found in both cytoplasmic and transmembrane proteins, play a vital role in ligand recognition and signal transduction. There are 12 TLRs, in which ten human isoforms of TLRs (TLR-1 to 10) have been identified. The LRR, which is deputed to recognition of the ligand, is composed of 19–25 tandem repeats of 24–29 amino acids, folded in strands and in helices that are linked by loops. 2 The transmembrane domain and TIR domain are highly conserved among the TLRs. 3