TLRs play a critical role in innate immunity since they are expressed not only in innate immune cells, but also in nonimmune cells including cancer cells. Functional TLR4 expression has been linked to HCC development. TLR4 may serve an important role in HCC cancer tumorigenesis by promoting the malignant transformation of epithelial cells and tumor growth. The consequences might be dependent on the complex signaling networks triggered by TLR4 activation and the tumor microenvironment. A few studies have suggested TLR4 as a target in the treatment of HCC. Based on these findings, agents targeting TLR4 together with other therapies may be considered the best approaches. Above all, the mechanisms of TLR4 signaling and crosstalk with other signaling pathways in the HCC microenvironment will definitely provide a promising novel strategy for cancer treatment.
The study was supported in part by the grant from the National Natural Science Foundation of China (number 81372668) and the Fundamental Research Funds for the Central Universities (2014QN064).
The authors report no conflicts of interest in this work.
Jing Yang,1 Min Li,2 Qi Chang Zheng2
1Department of First General Surgery, Gansu Provincial Hospital, Lanzhou, 2Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China.
1. Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol. 2014;28(5):753–770.
2. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48(6):2047–2063.
3. Igney FH, Krammer PH. Immune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol. 2002;71(6):907–920.
4. Liu W, Jing Y, Yu G, et al. Toll like receptor 4 facilitates invasion and migration as a cancer stem cell marker in hepatocellular carcinoma. Cancer Lett. 2014. pii: S0304-3835(14)00762-9.
5. Koike K, Tsutsumi T, Fujie H, Shintani Y, Kyoji M. Molecular mechanism of viral hepatocarcinogenesis. Oncology. 2002;62 Suppl 1:29–37.
6. Fausto N. Mouse liver tumorigenesis: models, mechanisms, and relevance to human disease. Semin Liver Dis. 1999;19(3):243–252.
7. Sakurai T, Maeda S, Chang L, Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A. 2006; 103(28):10544–10551.
8. Lavelle EC, Murphy C, O’Neill LA, Creagh EM. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol. 2010;3(1):17–28.
9. Rakoff-Nahoum S, Medzhitov R. Role of toll-like receptors in tissue repair and tumorigenesis. Biochemistry (Mosc). 2008;73(5):555–561.
10. Schreibelt G, Tel J, Sliepen KH, et al. Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunol Immunother. 2010;59(10):1573–1582.
11. Kabelitz D. Expression and function of Toll-like receptors in T lymphocytes. Curr Opin Immunol. 2007;19(1):39–45.
12. Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci U S A. 2006;103(18):7048–7053.
13. Sutmuller RP, den Brok MH, Kramer M, et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest. 2006;116(2):485–494.
14. Huang B, Zhao J, Li H, et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005;65(12):5009–5014.
15. Kelly MG, Alvero AB, Chen R, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66(7):3859–3868.
16. Keogh B, Parker AE. Toll-like receptors as targets for immune disorders. Trends Pharmacol Sci. 2011;32(7):435–442.
17. So EY, Ouchi T. The application of Toll like receptors for cancer therapy. Int J Biol Sci. 2010;6(7):675–681.
18. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–436.
19. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–759.
20. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376.
21. Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32(3):305–315.
22. Tsan MF. Toll-like receptors, inflammation and cancer. Semin Cancer Biol. 2006;16(1):32–37.
23. Sato Y, Goto Y, Narita N, Hoon DS. Cancer cells expressing toll-like receptors and the tumor microenvironment.Cancer Microenviron. 2009;2 Suppl 1:205–214.
24. Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13(11):1324–1332.
25. Tsung A, Sahai R, Tanaka H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005;201(7):1135–1143.
26. Tang D, Kang R, Zeh HJ 3rd, Lotze MT. High-mobility group box 1 and cancer. Biochim Biophys Acta. 2010;1799(1–2):131–140.
27. Stern R. Hyaluronidases in cancer biology. Semin Cancer Biol. 2008; 18(4):275–280.
28. Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007;220:35–46.
29. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.Nature. 2002;418(6894):191–195.
30. Sha Y, Zmijewski J, Xu Z, Abraham E. HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol. 2008;180(4):2531–2537.
31. Tian J, Avalos AM, Mao SY, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8(5):487–496.
32. Youn JH, Oh YJ, Kim ES, Choi JE, Shin JS. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes. J Immunol. 2008;180(7):5067–5074.
33. Yan W, Chang Y, Liang X, et al. High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology. 2012;55(6):1863–1875.
34. Jiang D, Liang J, Fan J, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173–1179.
35. Del Pozo JL. Primers on molecular pathways: lipopolysaccharide signaling – potential role in pancreatitis and pancreatic cancer. Pancreatology. 2010;10(2–3):114–118.
36. Ikebe M, Kitaura Y, Nakamura M, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol. 2009;100(8):725–731.
37. Loiarro M, Ruggiero V, Sette C. Targeting TLR/IL-1R signalling in human diseases. Mediators Inflamm. 2010;2010:674363.
38. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.
39. Lee MS, Kim YJ. Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem. 2007;76:447–480.
40. Mai CW, Kang YB, Pichika MR. 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. Onco Targets Ther. 2013;6:1573–1587.
41. Fu HY, Li C, Yang W, et al. FOXP3 and TLR4 protein expression are correlated in non-small cell lung cancer: implications for tumor progression and escape. Acta Histochem. 2013;115(2):151–157.
42. Tang X, Zhu Y. TLR4 signaling promotes immune escape of human colon cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Oncol Res. 2012;20(1):15–24.
43. Wang L, Zhao Y, Qian J, et al. Toll-like receptor-4 signaling in mantle cell lymphoma: effects on tumor growth and immune evasion. Cancer. 2013;119(4):782–791.
44. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48(1):322–335.
45. Matsumura T, Degawa T, Takii T, et al. TRAF6-NF-kappaB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes. Immunology. 2003;109(1):127–136.
46. Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology. 2003; 37(5):1043–1055.
47. Su GL, Klein RD, Aminlari A, et al. Kupffer cell activation by lipopolysaccharide in rats: role for lipopolysaccharide binding protein and toll-like receptor 4. Hepatology. 2000;31(4):932–936.
48. Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol. 2009;24(6):943–954.
49. Aoyama T, Paik YH, Seki E. Toll-like receptor signaling and liver fibrosis. Gastroenterol Res Pract. 2010;2010. pii: 192543.
50. Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115(1):56–65.
51. Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol. 2012;590(Pt 3):447–458.
52. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125–172.
53. Wang JP, Zhang Y, Wei X, et al. Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C. APMIS. 2010;118(4):261–270.
54. Wei XQ, Guo YW, Liu JJ, Wen ZF, Yang SJ, Yao JL. The significance of Toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B. Clin Invest Med. 2008;31(3):E123–E130.
55. Machida K, Tsukamoto H, Mkrtchyan H, et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci U S A. 2009; 106(5):1548–1553.
56. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes.Biol Pharm Bull. 2005; 28(5):886–892.
57. Jing YY, Han ZP, Sun K, et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012;10:98.
58. Yang J, Zhang JX, Wang H, Wang GL, Hu QG, Zheng QC. Hepatocellular carcinoma and macrophage interaction induced tumor immunosuppression via Treg requires TLR4 signaling. World J Gastroenterol. 2012;18(23):2938–2947.
59. EirÓ N, Altadill A, Juórez LM, et al. Toll-like receptors 3, 4 and 9 in hepatocellular carcinoma: Relationship with clinicopathological characteristics and prognosis. Hepatol Res. 2014;44(7):769–778.
60. Maeda S. NF-κB, JNK, and TLR signaling pathways in hepatocarcinogenesis. Gastroenterol Res Pract. 2010;2010:367694.
61. Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–124.
62. Wang L, Zhu R, Huang Z, Li H, Zhu H. Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci. 2013;58(8):2223–2236.
63. Yuan X, Zhou Y, Wang W, et al. Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production. Cell Death Dis. 2013;4:e794.
64. Gong W, Wang ZY, Chen GX, Liu YQ, Gu XY, Liu WW. Invasion potential of H22 hepatocarcinoma cells is increased by HMGB1-induced tumor NF-κB signaling via initiation of HSP70. Oncol Rep. 2013;30(3):1249–1256.
65. Minmin S, Xiaoqian X, Hao C, et al. Single nucleotide polymorphisms of Toll-like receptor 4 decrease the risk of development of hepatocellular carcinoma. PLoS One. 2011;6(4):e19466.
66. Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104(8):2224–2234.
67. Rossignol DP, Lynn M. Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue. J Endotoxin Res. 2002;8(6):483–488.
68. Yu P, Cheng X, Du Y, Huang L, Dong R. TAK-242 can be the potential agents for preventing invasion and metastasis of hepatocellular carcinoma. Med Hypotheses. 2013;81(4):653–655.
69. Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21(4):504–516.
70. Cowden JM, Yu F, Challapalli M, et al. Antagonism of the histamine H4 receptor reduces LPS-induced TNF production in vivo. Inflamm Res. 2013;62(6):599–607.
71. Huang S, He X. The role of microRNAs in liver cancer progression. Br J Cancer. 2011;104(2):235–240.
72. Li W, Xie L, He X, et al. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma.Int J Cancer. 2008;123(7):1616–1622.
73. McCoy CE, Sheedy FJ, Qualls JE, et al. IL-10 inhibits miR-155 induction by toll-like receptors. J Biol Chem. 2010;285(27):20492–20498.
Source: Journal of Hepatocellular Carcinoma.
Originally published on February 16, 2015.