Abstract
The tumor cell signaling pathways that trigger the uncontrolled proliferation, resistance to apoptosis, metastasis and escape from immune surveillance are partially understood. Toll-like receptors (TLRs), which recognize a variety of pathogen-associated molecular patterns, are centrally involved in the initiation of the innate and adaptive immune responses. However, recent evidence shows that functional TLRs are also expressed on a wide variety of tumors suggesting that TLRs may play important roles in tumor biology. Activation of tumor cell TLRs not only promotes tumor cell proliferation and resistance to apoptosis, but also enhances tumor cell invasion and metastasis by regulating metalloproteinases and integrins. Moreover, the activation of TLR signaling in tumor cells induces the synthesis of proinflammatory factors and immunosuppressive molecules, which enhance the resistance of tumor cells to cytotoxic lymphocyte attack and lead to immune evasion. Thus, the neoplastic process may usurp TLR signaling pathways to advance cancer progression, which suggests that targeting tumor TLR signaling pathways may open novel therapeutic avenues.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abiko Y, Mitamura J, Nishimura M, Muramatsu T, Inoue T, Shimono M et al. (1999). Pattern of expression of beta-defensins in oral squamous cell carcinoma. Cancer Lett 143: 37–43.
Akira S, Uematsu S, Takeuchi O . (2006). Pathogen recognition and innate immunity. Cell 124: 783–801.
Alexopoulou L, Holt AC, Medzhitov R, Flavell RA . (2001). Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732–738.
Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD et al. (1999). Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285: 736–739.
Andersen MH, Schrama D, Thor Straten P, Becker JC . (2006). Cytotoxic T cells. J Invest Dermatol 126: 32–41.
Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW et al. (2000). Hsp70 stimulates cytokine production through a CD-14-dependent pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6: 435–442.
Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S et al. (2005). Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 202: 1131–1139.
Berg AA . (2002). Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 23: 509–512.
Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O et al. (2002). Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2. Science 298: 1025–1029.
Bohnhorst J, Rasmussen T, Moen SH, Flottum M, Knudsen L, Borset M et al. (2006). Toll-like receptors mediate proliferation and survival of multiple myeloma cells. Leukemia 20: 1138–1144.
Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR . (2004). Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin–immunoglobulin G complexes. J Exp Med 199: 1631–1640.
Camilo R, Capelozzi VL, Siqueira SA, Del Carlo Bernardi F . (2006). Expression of p63, keratin 5/6, keratin 7, and surfactant-A in non-small cell lung carcinomas. Hum Pathol 37: 542–546.
Chen YC, Giovannucci E, Lazarus R, Kraft P, Ketkar S, Hunter DJ . (2005). Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res 65: 11771–11778.
Cheng I, Plummer SJ, Casey G, Witte JS . (2007). Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16: 352–355.
Ciocca DR, Calderwood SK . (2005). Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10: 86–103.
Craft N, Bruhn KW, Nguyen BD, Prins R, Lin JW, Liau LM et al. (2005). The TLR7 agonist imiquimod enhances the anti-melanoma effects of a recombinant Listeria monocytogenes vaccine. J Immunol 175: 1983–1990.
Dan HC, Jiang K, Coppola D, Hamilton A, Nicosia SV, Sebti SM et al. (2004a). Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. Oncogene 23: 706–715.
Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG et al. (2004b). Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem 279: 5405–5412.
Deane JA, Bolland S . (2006). Nucleic acid-sensing TLRs as modifiers of autoimmunity. J Immunol 177: 6573–6578.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al. (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8: 793–800.
Droemann D, Albrecht D, Gerdes J, Ulmer AJ, Branscheid D, Vollmer E et al. (2005). Human lung cancer cells express functionally active Toll-like receptor 9. Respir Res 6: 1–7.
Ehlers M, Ravetch JV . (2007). Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance. Trends Immunol 28: 74–79.
Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A et al. (2007). Masquerader: high mobility group box-1 and cancer. Clin Cancer Res 13: 2836–2848.
Ganz T, Weiss J . (1997). Antimicrobial peptides of phagocytes and epithelia. Semin Hematol 34: 343–354.
Gotte M, Yip GW . (2006). Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. Cancer Res 66: 10233–10237.
Gratas C, Tohma Y, Barnas C, Taniere P, Hainaut P, Ohgaki H . (1998). Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. Cancer Res 58: 2057–2062.
Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M . (2002). Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J Immunol 168: 5989–5992.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
Harmey JH, Bucana CD, Lu W, Byrne AM, McDonnell S, Lynch C et al. (2002). Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer 101: 415–422.
Hassan F, Islam S, Tumurkhuu G, Naiki Y, Koide N, Mori I et al. (2006). Intracellular expression of toll-like receptor 4 in neuroblastoma cells and their unresponsiveness to lipopolysaccharide. BMC Cancer 6: 281–287.
Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR et al. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410: 1099–1103.
He W, Liu Q, Wang L, Chen W, Li N, Cao X . (2007). TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol 44: 2850–2859.
Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S et al. (2004). Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303: 1526–1529.
Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H et al. (2000). A Toll-like receptor recognizes bacterial DNA. Nature 408: 740–745.
Hold GL, Rabkin CS, Chow WH, Smith MG, Gammon MD, Risch HA et al. (2007). A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors. Gastroenterology 132: 905–912.
Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH et al. (2005). Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65: 5009–5014.
Huang B, Zhao J, Shen S, Li H, He KL, Shen GX et al. (2007). Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Res 67: 4346–4352.
Iino N, Matsunaga T, Harada T, Igarashi S, Koyama I, Komoda T . (2007). Comparative characterization of pulmonary surfactant aggregates and alkaline phosphatase isozymes in human lung carcinoma tissue. Cell Tissue Res 328: 355–363.
Ilvesaro JM, Merrell MA, Swain TM, Davidson J, Zayzafoon M, Harris KW et al. (2007). Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate 67: 774–781.
Iwasaki A, Medzhitov R . (2004). Toll-like receptor control of the adaptive immune responses. Nat Immunol 5: 987–995.
Jego G, Bataille R, Geffroy-Luseau A, Descamps G, Pellat-Deceunynck C . (2006). Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Leukemia 20: 1130–1137.
Johnson GB, Brunn GJ, Kodaira Y, Platt JL . (2002). Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J Immunol 168: 5233–5239.
Kabelitz D . (2007). Expression and function of Toll-like receptors in T lymphocytes. Curr Opin Immunol 19: 39–45.
Kariko K, Ni H, Capodici J, Lamphier M, Weissman D . (2004). mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 279: 12542–12550.
Kawai T, Akira S . (2005). Pathogen recognition with Toll-like receptors. Curr Opin Immunol 17: 338–344.
Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S et al. (2006). TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 66: 3859–3868.
Khazaie K, von Boehmer H . (2006). The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer. Semin Cancer Biol 16: 124–136.
Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA . (2000). Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 164: 13–17.
Krieg AM . (2007). Development of TLR9 agonists for cancer therapy. J Clin Invest 117: 1184–1194.
Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA et al. (2003). Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 100: 6646–6651.
Lee JW, Choi JJ, Seo ES, Kim MJ, Kim WY, Choi CH et al. (2007). Increased toll-like receptor 9 expression in cervical neoplasia. Mol Carcinog 46: 941–947.
Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA . (2006). Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24: 99–146.
Liu H, Komai-Koma M, Xu D, Liew FY . (2006). Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 103: 7048–7053.
Liu Y, Huang B, Yuan Y, Gong W, Xiao H, Li D et al. (2007). Inhibition of hepatocarcinoma and tumor metastasis to liver by gene therapy with recombinant CBD-HepII polypeptide of fibronectin. Int J Cancer 121: 184–192.
Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R . (2005). Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 52: 2936–2946.
Lizee G, Radvanyi LG, Overwijk WW, Hwu P . (2006). Improving anti-tumor immune responses by circumventing immunoregulatory cells and mechanisms. Clin Cancer Res 12: 4794–4803.
Marshak-Rothstein A . (2006). Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6: 823–835.
Mellor A, Baban B, Chandler P, Manlapat A, Kahler D, Munn D . (2005). CpG oligonucleotides induce splenic CD19+ DCs to acquire IDO-dependent T cell regulatory functions via IFN signaling. J Immunol 175: 5601–5605.
Merrell MA, Ilvesaro JM, Lehtonen N, Sorsa T, Gehrs B, Rosenthal E et al. (2006). Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res 4: 437–447.
Miyake K . (2007). Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 19: 3–10.
Molteni M, Marabella D, Orlandi C, Rossetti C . (2006). Melanoma cell lines are responsive in vitro to lipopolysaccharide and express TLR-4. Cancer Lett 235: 75–83.
Munn DH, Mellor AL . (2007). Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117: 1147–1154.
Nieters A, Beckmann L, Deeg E, Becker N . (2006). Gene polymorphisms in Toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk. Genes Immun 7: 615–624.
Ohara T, Morishita T, Suzuki H, Hibi T . (2006). Heterozygous Thr 135 Ala polymorphism at leucine-rich repeat (LRR) in genomic DNA of toll-like receptor 4 in patients with poorly-differentiated gastric adenocarcinomas. Int J Mol Med 18: 59–63.
Okamoto M, Oshikawa T, Tano T, Ahmed SU, Kan S, Sasai A et al. (2006). Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis and Toll-like receptor 4 signaling. J Immunother 29: 78–86.
Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J et al. (2001). The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 276: 10229–10233.
O'Neill LA . (2006). How Toll-like receptors signal: what we know and what we don't know. Curr Opin Immunol 18: 3–9.
Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A et al. (2004). Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279: 7370–7377.
Pasare C, Medzhitov R . (2003). Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299: 1033–1036.
Pashenkov M, Goess G, Wagner C, Hormann M, Jandl T, Moser A et al. (2006). Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J Clin Oncol 24: 5716–5724.
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X et al. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085–2088.
Rifkin IR, Leaderbetter EA, Busconi L, Viglanti G, Marshk-Rothstein A . (2005). Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 204: 27–42.
Roelofs MF, Boelens WC, Joosten LA, Abdollahi-Roodsaz S, Geurts J, Wunderink LU et al. (2006). Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J Immunol 176: 7021–7027.
Rouas-Freiss N, Moreau P, Menier C, Carosella ED . (2003). HLA-G in cancer: a way to turn off the immune system. Semin Cancer Biol 13: 325–336.
Rybarczyk BJ, Simpson-Haidaris PJ . (2000). Fibrinogen assembly, secretion, and deposition into extracellular matrix by MCF-7 human breast carcinoma cells. Cancer Res 60: 2033–2039.
Sanderson RD, Yang Y, Suva LJ, Kelly T . (2004). Heparan sulfate proteoglycans and heparanase—partners in osteolytic tumor growth and metastasis. Matrix Biol 23: 341–352.
Schmausser B, Andrulis M, Endrich S, Muller-Hermelink HK, Eck M . (2005). Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Int J Med Microbiol 295: 179–185.
Serafini P, Borrello I, Bronte V . (2006). Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16: 53–65.
Singh-Jasuja H, Scherer HU, Hilf N, Arnold-Schild D, Rammensee HG, Toes RE et al. (2000). The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur J Immunol 30: 2211–2215.
Sioud M . (2006). Innate sensing of self and nonself RNAs by Toll-like receptors. Trends Mol Med 12: 167–176.
Smiley ST, King JA, Hancock WW . (2001). Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J Immunol 167: 2887–2894.
Song C, Chen LZ, Zhang RH, Yu XJ, Zeng YX . (2006). Functional variant in the 3′-untranslated region of Toll-like receptor 4 is associated with nasopharyngeal carcinoma risk. Cancer Biol Ther 5: 1285–1291.
Sun J, Wiklund F, Zheng SL, Chang B, Balter K, Li L et al. (2005). Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J Natl Cancer Inst 97: 525–532.
Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ et al. (2006). Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116: 485–494.
Szczepanski M, Stelmachowska M, Stryczynski L, Golusinski W, Samara H, Mozer-Lisewska I et al. (2007). Assessment of expression of toll-like receptors 2, 3 and 4 in laryngeal carcinoma. Eur Arch Otorhinolaryngol 264: 525–530.
Takeda K, Akira S . (2004). TLR signaling pathways. Semin Immunol 16: 3–9.
Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T et al. (2002). Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J Exp Med 195: 99–111.
Tsan MF, Gao B . (2004). Endogenous ligands of Toll-like receptors. J Leukoc Biol 76: 514–519.
Tsan MF, Gao B . (2007). Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. J Endotoxin Res 13: 6–14.
Vicari AP, Caux C, Trinchieri G . (2002). Tumor escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 12: 33–42.
Wang HY, Wang RF . (2007). Regulatory T cells and cancer. Curr Opin Immunol 19: 217–223.
Wang JH, Manning BJ, Wu QD, Blankson S, Bouchier-Hayes D, Redmond HP . (2003). Endotoxin/lipopolysaccharide activates NF-kappaB and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J Immunol 170: 795–804.
Whitmore MM, DeVeer MJ, Edling A, Oates RK, Simons B, Lindner D et al. (2004). Synergistic activation of innate immunity by double-stranded RNA and CpG DNA promotes enhanced anti-tumor activity. Cancer Res 64: 5850–5860.
Whitmore MM, Li S, Falo Jr L, Huang L . (2001). Systemic administration of LPD prepared with CpG oligonucleotides inhibits the growth of established pulmonary metastases by stimulating innate and acquired anti-tumor immune responses. Cancer Immunol Immunother 50: 503–514.
Wingender G, Garbi N, Schumak B, Jungerkes F, Endl E, von Bubnoff D et al. (2006). Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO. Eur J Immunol 36: 12–20.
Wu JD, Higgins LM, Steinle A, Cosman D, Haugk K, Plymate SR . (2004). Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Inves 114: 560–568.
Xu Q . (2002). Role of heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol 22: 1547–1559.
Yang Y, Huang CT, Huang X, Pardoll DM . (2004). Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 5: 508–515.
Yu H, Kortylewski M, Pardoll D . (2007). Crosstalk between cancer and immune cells: role of STAT3 in the tumor microenvironment. Nat Rev Immunol 7: 41–51.
Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV, Cheng JQ . (2003). AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. J Biol Chem 278: 23432–23440.
Zheng SL, Augustsson-Balter K, Chang B, Hedelin M, Li L, Adami HO et al. (2004). Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the Cancer Prostate in Sweden Study. Cancer Res 64: 2918–2922.
Zhou XX, Jia WH, Shen GP, Qin HD, Yu XJ, Chen LZ et al. (2006). Sequence variants in toll-like receptor 10 are associated with nasopharyngeal carcinoma risk. Cancer Epidemiol Biomarkers Prev 15: 862–866.
Acknowledgements
Dr Huabao Xiong was supported by NIH P01 DK72201, a Crohn's and Colitis Foundation of America, a grant from the Eli and Edythe L Broad Foundation. Dr Zuo-Hua Feng was supported by National Development Program (973) For Key Basic Research (2002CB513100) of China. Dr Jay Unkeless was supported by a Crohn's and Colitis Foundation of America Grant.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Huang, B., Zhao, J., Unkeless, J. et al. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 27, 218–224 (2008). https://doi.org/10.1038/sj.onc.1210904
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210904
Keywords
This article is cited by
-
Development of a TLR-Based Model That Can Predict Prognosis, Tumor Microenvironment, and Drug Response for Esophageal Squamous Cell Carcinoma
Biochemical Genetics (2024)
-
Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer
npj Precision Oncology (2023)
-
Pattern recognition receptors and their nano-adjuvants for cancer immunotherapy
Journal of Pharmaceutical Investigation (2023)
-
Toll-like receptor 9 negatively related to clinical outcome of AML patients
Journal of the Egyptian National Cancer Institute (2020)
-
Targeting innate sensing in the tumor microenvironment to improve immunotherapy
Cellular & Molecular Immunology (2020)