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Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

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Abstract

Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis.

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References

  • Akira, S., Uematsu, S., and Takeuchi, O., Pathogen recognition and innate immunity. Cell, 124, 783–801 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Balkwill, F. and Coussens, L. M., Cancer: an inflammatory link. Nature, 431, 405–406 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Balkwill, F. and Mantovani, A., Inflammation and cancer: back to Virchow? Lancet, 357, 539–545 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Basith, S., Manavalan, B., Lee, G., Kim, S. G., and Choi, S., Toll-like receptor modulators: a patent review (2006–2010). Expert Opin. Ther. Pat., 21, 927–944 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Bassi, P., BCG (Bacillus of Calmette Guerin) therapy of highrisk superficial bladder cancer. Surg. Oncol., 11, 77–83 (2002).

    Article  PubMed  Google Scholar 

  • Bauer, A. K., Dixon, D., Degraff, L. M., Cho, H. Y., Walker, C. R., Malkinson, A. M., and Kleeberger, S. R., Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J. Natl. Cancer Inst., 97, 1778–1781 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Beg, A. A., Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol., 23, 509–512 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Berger, R., Fiegl, H., Goebel, G., Obexer, P., Ausserlechner, M., Doppler, W., Hauser-Kronberger, C., Reitsamer, R., Egle, D., Reimer, D., Muller-Holzner, E., Jones, A., and Widschwendter, M., Toll-like receptor 9 expression in breast and ovarian cancer is associated with poorly differentiated tumors. Cancer Sci., 101, 1059–1066 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Blander, J. M. and Medzhitov, R., Regulation of phagosome maturation by signals from toll-like receptors. Science, 304, 1014–1018 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Brignole, C., Marimpietri, D., Di Paolo, D., Perri, P., Morandi, F., Pastorino, F., Zorzoli, A., Pagnan, G., Loi, M., Caffa, I., Erminio, G., Haupt, R., Gambini, C., Pistoia, V., and Ponzoni, M., Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma. Cancer Res., 70, 9816–9826 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Burdelya, L. G., Krivokrysenko, V. I., Tallant, T. C., Strom, E., Gleiberman, A. S., Gupta, D., Kurnasov, O. V., Fort, F. L., Osterman, A. L., Didonato, J. A., Feinstein, E., and Gudkov, A. V., An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science, 320, 226–230 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Butts, C., Maksymiuk, A., Goss, G., Soulieres, D., Marshall, E., Cormier, Y., Ellis, P. M., Price, A., Sawhney, R., Beier, F., Falk, M., and Murray, N., Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial. J. Cancer Res. Clin. Oncol., 137, 1337–1342 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Butts, C., Murray, N., Maksymiuk, A., Goss, G., Marshall, E., Soulieres, D., Cormier, Y., Ellis, P., Price, A., Sawhney, R., Davis, M., Mansi, J., Smith, C., Vergidis, D., Ellis, P., Macneil, M., and Palmer, M., Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-smallcell lung cancer. J. Clin. Oncol., 23, 6674–6681 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Cai, Z., Sanchez, A., Shi, Z., Zhang, T., Liu, M., and Zhang, D., Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res., 71, 2466–2475 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Chen, R., Alvero, A. B., Silasi, D. A., and Mor, G., Inflammation, cancer and chemoresistance: taking advantage of the tolllike receptor signaling pathway. Am. J. Reprod. Immunol., 57, 93–107 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Chen, R., Alvero, A. B., Silasi, D. A., Steffensen, K. D., and Mor, G., Cancers take their Toll—the function and regulation of Toll-like receptors in cancer cells. Oncogene, 27, 225–233 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Chen, Y. C., Giovannucci, E., Lazarus, R., Kraft, P., Ketkar, S., and Hunter, D. J., Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res., 65, 11771–11778 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Cherfils-Vicini, J., Platonova, S., Gillard, M., Laurans, L., Validire, P., Caliandro, R., Magdeleinat, P., Mami-Chouaib, F., Dieu-Nosjean, M. C., Fridman, W. H., Damotte, D., Sautes-Fridman, C., and Cremer, I., Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J. Clin. Invest., 120, 1285–1297 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Chuang, J. H., Chuang, H. C., Huang, C. C., Wu, C. L., Du, Y. Y., Kung, M. L., Chen, C. H., Chen, S. C., and Tai, M. H., Differential toll-like receptor 3 (TLR3) expression and apoptotic response to TLR3 agonist in human neuroblastoma cells. J. Biomed. Sci., 18, 65 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Coley, F. C., A Pseudo-Hypertrophic Family. Br. Med. J., 1, 399–400 (1894).

    Article  PubMed  CAS  Google Scholar 

  • Coussens, L. M. and Werb, Z., Inflammation and cancer. Nature, 420, 860–867 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Czerniecki, B. J., Koski, G. K., Koldovsky, U., Xu, S., Cohen, P. A., Mick, R., Nisenbaum, H., Pasha, T., Xu, M., Fox, K. R., Weinstein, S., Orel, S. G., Vonderheide, R., Coukos, G., Demichele, A., Araujo, L., Spitz, F. R., Rosen, M., Levine, B. L., June, C., and Zhang, P. J., Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res., 67, 1842–1852 (2007).

    Article  PubMed  CAS  Google Scholar 

  • D’agostini, C., Pica, F., Febbraro, G., Grelli, S., Chiavaroli, C., and Garaci, E., Antitumour effect of OM-174 and cyclophosphamide on murine B16 melanoma in different experimental conditions. Int. Immunopharmacol., 5, 1205–1212 (2005).

    Article  PubMed  CAS  Google Scholar 

  • D’souza, G., Kreimer, A. R., Viscidi, R., Pawlita, M., Fakhry, C., Koch, W. M., Westra, W. H., and Gillison, M. L., Casecontrol study of human papillomavirus and oropharyngeal cancer. N. Engl. J. Med., 356, 1944–1956 (2007).

    Article  PubMed  Google Scholar 

  • De Cesare, M., Calcaterra, C., Pratesi, G., Gatti, L., Zunino, F., Menard, S., and Balsari, A., Eradication of ovarian tumor xenografts by locoregional administration of targeted immunotherapy. Clin. Cancer Res., 14, 5512–5518 (2008).

    Article  PubMed  Google Scholar 

  • Doan, H. Q., Bowen, K. A., Jackson, L. A., and Evers, B. M., Toll-like receptor 4 activation increases Akt phosphorylation in colon cancer cells. Anticancer Res., 29, 2473–2478 (2009).

    PubMed  CAS  Google Scholar 

  • Dorn, A. and Kippenberger, S., Clinical application of CpG-, non-CpG-, and antisense oligodeoxynucleotides as immunomodulators. Curr. Opin. Mol. Ther., 10, 10–20 (2008).

    PubMed  CAS  Google Scholar 

  • Droemann, D., Albrecht, D., Gerdes, J., Ulmer, A. J., Branscheid, D., Vollmer, E., Dalhoff, K., Zabel, P., and Goldmann, T., Human lung cancer cells express functionally active Tolllike receptor 9. Respir. Res., 6, 1 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Dummer, R., Hauschild, A., Becker, J. C., Grob, J. J., Schadendorf, D., Tebbs, V., Skalsky, J., Kaehler, K. C., Moosbauer, S., Clark, R., Meng, T. C., and Urosevic, M., An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin. Cancer Res., 14, 856–864 (2008).

    Article  PubMed  CAS  Google Scholar 

  • El-Omar, E. M., Ng, M. T., and Hold, G. L., Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene, 27, 244–252 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Ellerman, J. E., Brown, C. K., De Vera, M., Zeh, H. J., Billiar, T., Rubartelli, A., and Lotze, M. T., Masquerader: high mobility group box-1 and cancer. Clin. Cancer Res., 13, 2836–2848 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Fukata, M., Chen, A., Vamadevan, A. S., Cohen, J., Breglio, K., Krishnareddy, S., Hsu, D., Xu, R., Harpaz, N., Dannenberg, A. J., Subbaramaiah, K., Cooper, H. S., Itzkowitz, S. H., and Abreu, M. T., Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology, 133, 1869–1881 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Garay, R. P., Viens, P., Bauer, J., Normier, G., Bardou, M., Jeannin, J. F., and Chiavaroli, C., Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur. J. Pharmacol., 563, 1–17 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Geddes, K., Magalhaes, J. G., and Girardin, S. E., Unleashing the therapeutic potential of NOD-like receptors. Nat. Rev. Drug Discov., 8, 465–479 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Reyes, S., Fernandez, J. M., Gonzalez, L. O., Aguirre, A., Suarez, A., Gonzalez, J. M., Escaff, S., and Vizoso, F. J., Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence. Cancer Immunol. Immunother., 60, 217–226 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Reyes, S., Marin, L., Gonzalez, L., Gonzalez, L. O., Del Casar, J. M., Lamelas, M. L., Gonzalez-Quintana, J. M., and Vizoso, F. J., Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer, 10, 665 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Goodchild, A., Nopper, N., Craddock, A., Law, T., King, A., Fanning, G., Rivory, L., and Passioura, T., Primary leukocyte screens for innate immune agonists. J. Biomol. Screen., 14, 723–730 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Gorden, K. K., Qiu, X. X., Binsfeld, C. C., Vasilakos, J. P., and Alkan, S. S., Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J. Immunol., 177, 6584–6587 (2006).

    PubMed  CAS  Google Scholar 

  • Goto, Y., Arigami, T., Kitago, M., Nguyen, S. L., Narita, N., Ferrone, S., Morton, D. L., Irie, R. F., and Hoon, D. S., Activation of Toll-like receptors 2, 3, and 4 on human melanoma cells induces inflammatory factors. Mol. Cancer Ther., 7, 3642–3653 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Grimm, M., Kim, M., Rosenwald, A., Heemann, U., Germer, C. T., Waaga-Gasser, A. M., and Gasser, M., Toll-like receptor (TLR) 7 and TLR8 expression on CD133+ cells in colorectal cancer points to a specific role for inflammation-induced TLRs in tumourigenesis and tumour progression. Eur. J. Cancer, 46, 2849–2857 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Guo, Z., Chen, L., Zhu, Y., Zhang, Y., He, S., Qin, J., Tang, X., Zhou, J., and Wei, Y., Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and. Oncol. Rep., 27, 396–402 (2012).

    PubMed  CAS  Google Scholar 

  • Hanahan, D. and Weinberg, R. A., The hallmarks of cancer. Cell, 100, 57–70 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Hanten, J. A., Vasilakos, J. P., Riter, C. L., Neys, L., Lipson, K. E., Alkan, S. S., and Birmachu, W., Comparison of human B cell activation by TLR7 and TLR9 agonists. BMC Immunol., 9, 39 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Harmey, J. H., Bucana, C. D., Lu, W., Byrne, A. M., Mcdonnell, S., Lynch, C., Bouchier-Hayes, D., and Dong, Z., Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int. J. Cancer, 101, 415–422 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Harrison, L. I., Astry, C., Kumar, S., and Yunis, C., Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans. J. Clin. Pharmacol., 47, 962–969 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Hassan, F., Islam, S., Tumurkhuu, G., Naiki, Y., Koide, N., Mori, I., Yoshida, T., and Yokochi, T., Intracellular expression of toll-like receptor 4 in neuroblastoma cells and their unresponsiveness to lipopolysaccharide. BMC Cancer, 6, 281 (2006).

    Article  PubMed  CAS  Google Scholar 

  • He, J. F., Jia, W. H., Fan, Q., Zhou, X. X., Qin, H. D., Shugart, Y. Y., and Zeng, Y. X., Genetic polymorphisms of TLR3 are associated with Nasopharyngeal carcinoma risk in Cantonese population. BMC Cancer, 7, 194 (2007a).

    Article  PubMed  CAS  Google Scholar 

  • He, W., Liu, Q., Wang, L., Chen, W., Li, N., and Cao, X., TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol. Immunol., 44, 2850–2859 (2007b).

    Article  PubMed  CAS  Google Scholar 

  • Hernandez, Y., Sotolongo, J., Breglio, K., Conduah, D., Chen, A., Xu, R., Hsu, D., Ungaro, R., Hayes, L. A., Pastorini, C., Abreu, M. T., and Fukata, M., The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitisassociated neoplasia. BMC Gastroenterol., 10, 82 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Hold, G. L., Rabkin, C. S., Chow, W. H., Smith, M. G., Gammon, M. D., Risch, H. A., Vaughan, T. L., Mccoll, K. E., Lissowska, J., Zatonski, W., Schoenberg, J. B., Blot, W. J., Mowat, N. A., Fraumeni, J. F., Jr., and El-Omar, E. M., A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors. Gastroenterology, 132, 905–912 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Hua, D., Liu, M. Y., Cheng, Z. D., Qin, X. J., Zhang, H. M., Chen, Y., Qin, G. J., Liang, G., Li, J. N., Han, X. F., and Liu, D. X., Small interfering RNA-directed targeting of Toll-like receptor 4 inhibits human prostate cancer cell invasion, survival, and tumorigenicity. Mol. Immunol., 46, 2876–2884 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Huang, B., Zhao, J., Li, H., He, K. L., Chen, Y., Chen, S. H., Mayer, L., Unkeless, J. C., and Xiong, H., Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res., 65, 5009–5014 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Huang, B., Zhao, J., Shen, S., Li, H., He, K. L., Shen, G. X., Mayer, L., Unkeless, J., Li, D., Yuan, Y., Zhang, G. M., Xiong, H., and Feng, Z. H., Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Res., 67, 4346–4352 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Huang, B., Zhao, J., Unkeless, J. C., Feng, Z. H., and Xiong, H., TLR signaling by tumor and immune cells: a doubleedged sword. Oncogene, 27, 218–224 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Ilvesaro, J. M., Merrell, M. A., Swain, T. M., Davidson, J., Zayzafoon, M., Harris, K. W., and Selander, K. S., Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate, 67, 774–781 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Ioannou, S. and Voulgarelis, M., Toll-like receptors, tissue injury, and tumourigenesis. Mediators Inflamm, 2010 (2010).

  • Ishii, K. J., Kawakami, K., Gursel, I., Conover, J., Joshi, B. H., Klinman, D. M., and Puri, R. K., Antitumor therapy with bacterial DNA and toxin: complete regression of established tumor induced by liposomal CpG oligodeoxynucleotides plus interleukin-13 cytotoxin. Clin. Cancer Res., 9, 6516–6522 (2003).

    CAS  Google Scholar 

  • Janeway, C. A., Jr. and Medzhitov, R., Innate immune recognition. Annu. Rev. Immunol., 20, 197–216 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Jego, G., Bataille, R., Geffroy-Luseau, A., Descamps, G., and Pellat-Deceunynck, C., Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Leukemia, 20, 1130–1137 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Jiang, Q., Wei, H., and Tian, Z., Poly I:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway. BMC Cancer, 8, 12 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Johnson, G. B., Brunn, G. J., Tang, A. H., and Platt, J. L., Evolutionary clues to the functions of the Toll-like family as surveillance receptors. Trends Immunol., 24, 19–24 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Kagan, J. C., Su, T., Horng, T., Chow, A., Akira, S., and Medzhitov, R., TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat. Immunol., 9, 361–368 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Kanczkowski, W., Tymoszuk, P., Ehrhart-Bornstein, M., Wirth, M. P., Zacharowski, K., and Bornstein, S. R., Abrogation of TLR4 and CD14 expression and signaling in human adrenocortical tumors. J. Clin. Endocrinol. Metab., 95, E421–E429 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Kawai, T. and Akira, S., Pathogen recognition with Toll-like receptors. Curr. Opin. Immunol., 17, 338–344 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Kawai, T. and Akira, S., The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol., 11, 373–384 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Kelly, M. G., Alvero, A. B., Chen, R., Silasi, D. A., Abrahams, V. M., Chan, S., Visintin, I., Rutherford, T., and Mor, G., TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res., 66, 3859–3868 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Kikkawa, F., Kawai, M., Oguchi, H., Kojima, M., Ishikawa, H., Iwata, M., Maeda, O., Tomoda, Y., Arii, Y., Kuzuya, K., and Ohta, M., Ishizuka, T., Hattori, S.-E., and Aoki, K., Randomised study of immunotherapy with OK-432 in uterine cervical carcinoma. Eur. J. Cancer, 29A, 1542–1546 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Killeen, S. D., Wang, J. H., Andrews, E. J., and Redmond, H. P., Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system. Br. J. Cancer, 100, 1589–1602 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Kim, S., Takahashi, H., Lin, W. W., Descargues, P., Grivennikov, S., Kim, Y., Luo, J. L., and Karin, M., Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature, 457, 102–106 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Kim, W. Y., Lee, J. W., Choi, J. J., Choi, C. H., Kim, T. J., Kim, B. G., Song, S. Y., and Bae, D. S., Increased expression of Toll-like receptor 5 during progression of cervical neoplasia. Int. J. Gynecol. Cancer, 18, 300–305 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Kochling, J., Prada, J., Bahrami, M., Stripecke, R., Seeger, K., Henze, G., Wittig, B., and Schmidt, M., Anti-tumor effect of DNA-based vaccination and dSLIM immunomodulatory molecules in mice with Ph+ acute lymphoblastic leukaemia. Vaccine, 26, 4669–4675 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Krieg, A. M., Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene, 27, 161–167 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Kundu, S. D., Lee, C., Billips, B. K., Habermacher, G. M., Zhang, Q., Liu, V., Wong, L. Y., Klumpp, D. J., and Thumbikat, P., The toll-like receptor pathway: a novel mechanism of infection-induced carcinogenesis of prostate epithelial cells. Prostate, 68, 223–229 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Kutikhin, A. G., Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk. Hum. Immunol., 72, 1095–1116 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Lee, J. W., Choi, J. J., Seo, E. S., Kim, M. J., Kim, W. Y., Choi, C. H., Kim, T. J., Kim, B. G., Song, S. Y., and Bae, D. S., Increased toll-like receptor 9 expression in cervical neoplasia. Mol. Carcinog., 46, 941–947 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Lee, M. S. and Kim, Y. J., Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem., 76, 447–480 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M., and Hoffmann, J. A., The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell, 86, 973–983 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Levenga, J., De Vrij, F. M., Oostra, B. A., and Willemsen, R., Potential therapeutic interventions for fragile X syndrome. Trends Mol. Med., 16, 516–527 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Lowe, E. L., Crother, T. R., Rabizadeh, S., Hu, B., Wang, H., Chen, S., Shimada, K., Wong, M. H., Michelsen, K. S., and Arditi, M., Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS One, 5, e13027 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Lu, H., Dietsch, G. N., Matthews, M. A., Yang, Y., Ghanekar, S., Inokuma, M., Suni, M., Maino, V. C., Henderson, K. E., Howbert, J. J., Disis, M. L., and Hershberg, R. M., VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin. Cancer Res., 18, 499–509 (2012).

    Article  PubMed  CAS  Google Scholar 

  • Luo, J. L., Maeda, S., Hsu, L. C., Yagita, H., and Karin, M., Inhibition of NF-kappaB in cancer cells converts inflammationinduced tumor growth mediated by TNFalpha to TRAILmediated tumor regression. Cancer Cell, 6, 297–305 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Maehara, Y., Okuyama, T., Kakeji, Y., Baba, H., Furusawa, M., and Sugimachi, K., Postoperative immunochemotherapy including streptococcal lysate OK-432 is effective for patients with gastric cancer and serosal invasion. Am. J. Surg., 168, 36–40 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Manavalan, B., Basith, S., and Choi, S., Similar structures but different roles — an updated perspective on TLR structures. Front. Physiol., 2, 41 (2011).

    Article  PubMed  Google Scholar 

  • Mantovani, A., Allavena, P., Sica, A., and Balkwill, F., Cancerrelated inflammation. Nature, 454, 436–444 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Marodi, L., Neonatal innate immunity to infectious agents. Infect. Immun., 74, 1999–2006 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Mata-Haro, V., Cekic, C., Martin, M., Chilton, P. M., Casella, C. R., and Mitchell, T. C., The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science, 316, 1628–1632 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Matijevic, T., Marjanovic, M., and Pavelic, J., Functionally active toll-like receptor 3 on human primary and metastatic cancer cells. Scand. J. Immunol., 70, 18–24 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Matzinger, P., Tolerance, danger, and the extended family. Annu. Rev. Immunol., 12, 991–1045 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Matzinger, P., The danger model: a renewed sense of self. Science, 296, 301–305 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Mccall, K. D., Harii, N., Lewis, C. J., Malgor, R., Kim, W. B., Saji, M., Kohn, A. D., Moon, R. T., and Kohn, L. D., High basal levels of functional toll-like receptor 3 (TLR3) and noncanonical Wnt5a are expressed in papillary thyroid cancer and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology, 148, 4226–4237 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Medzhitov, R., Preston-Hurlburt, P., and Janeway, C. A., Jr., A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 388, 394–397 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C., Ghosh, S., and Janeway, C. A., Jr., MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell, 2, 253–258 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Merrell, M. A., Ilvesaro, J. M., Lehtonen, N., Sorsa, T., Gehrs, B., Rosenthal, E., Chen, D., Shackley, B., Harris, K. W., and Selander, K. S., Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol. Cancer Res., 4, 437–447 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Miyake, K., Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin. Immunol., 19, 3–10 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Molteni, M., Marabella, D., Orlandi, C., and Rossetti, C., Melanoma cell lines are responsive in vitro to lipopolysaccharide and express TLR-4. Cancer Lett., 235, 75–83 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Morales, A., Eidinger, D., and Bruce, A. W., Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116, 180–183 (1976).

    PubMed  CAS  Google Scholar 

  • Murata, M., Activation of Toll-like receptor 2 by a novel preparation of cell wall skeleton from Mycobacterium bovis BCG Tokyo (SMP-105) sufficiently enhances immune responses against tumors. Cancer Sci., 99, 1435–1440 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Ng, L. K., Rich, A. M., Hussaini, H. M., Thomson, W. M., Fisher, A. L., Horne, L. S., and Seymour, G. J., Toll-like receptor 2 is present in the microenvironment of oral squamous cell carcinoma. Br. J. Cancer, 104, 460–463 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Nomi, N., Kodama, S., and Suzuki, M., Toll-like receptor 3 signaling induces apoptosis in human head and neck cancer via survivin associated pathway. Oncol. Rep., 24, 225–231 (2010).

    PubMed  CAS  Google Scholar 

  • O’neill, L. A., How Toll-like receptors signal: what we know and what we don’t know. Curr. Opin. Immunol., 18, 3–9 (2006).

    Article  PubMed  CAS  Google Scholar 

  • O’neill, L. A., Fitzgerald, K. A., and Bowie, A. G., The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol., 24, 286–290 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Okamoto, H., Shoin, S., Koshimura, S., and Shimizu, R., Studies on the anticancer and streptolysin S-forming abilities of hemolytic streptococci. Jpn. J. Microbiol., 11, 323–326 (1967).

    PubMed  CAS  Google Scholar 

  • Okamoto, M., Oshikawa, T., Tano, T., Ohe, G., Furuichi, S., Nishikawa, H., Ahmed, S. U., Akashi, S., Miyake, K., Takeuchi, O., Akira, S., Moriya, Y., Matsubara, S., Ryoma, Y., Saito, M., and Sato, M., Involvement of Toll-like receptor 4 signaling in interferon-gamma production and antitumor effect by streptococcal agent OK-432. J. Natl. Cancer Inst., 95, 316–26 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Pandey, S. and Agrawal, D. K., Immunobiology of Toll-like receptors: emerging trends. Immunol. Cell Biol., 84, 333–341 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Panter, G., Kuznik, A., and Jerala, R., Therapeutic applications of nucleic acids as ligands for Toll-like receptors. Curr. Opin. Mol. Ther., 11, 133–145 (2009).

    PubMed  CAS  Google Scholar 

  • Picker, L. J. and Butcher, E. C., Physiological and molecular mechanisms of lymphocyte homing. Annu. Rev. Immunol., 10, 561–591 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., and Ben-Neriah, Y., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature, 431, 461–466 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Pimentel-Nunes, P., Afonso, L., Lopes, P., Roncon-Albuquerque, R., Jr., Goncalves, N., Henrique, R., Moreira-Dias, L., Leite-Moreira, A. F., and Dinis-Ribeiro, M. Increased expression of toll-like receptors (TLR) 2, 4 and 5 in gastric dysplasia. Pathol. Oncol. Res., 17, 677–683 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., and Beutler, B., Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science, 282, 2085–2088 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Qian, Y., Deng, J., Xie, H., Geng, L., Zhou, L., Wang, Y., Yin, S., Feng, X., and Zheng, S. Regulation of TLR4-induced IL-6 response in bladder cancer cells by opposing actions of MAPK and PI3K signaling. J. Cancer Res. Clin. Oncol., 135, 379–386 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Rakoff-Nahoum, S. and Medzhitov, R., Toll-like receptors and cancer. Nat. Rev. Cancer, 9, 57–63 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Rhee, S. H., Im, E., and Pothoulakis, C., Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology, 135, 518–528 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Ronkainen, H., Hirvikoski, P., Kauppila, S., Vuopala, K. S., Paavonen, T. K., Selander, K. S., and Vaarala, M. H., Absent Toll-like receptor-9 expression predicts poor prognosis in renal cell carcinoma. J. Exp. Clin. Cancer Res., 30, 84 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Salaun, B., Coste, I., Rissoan, M. C., Lebecque, S. J., and Renno, T., TLR3 can directly trigger apoptosis in human cancer cells. J. Immunol., 176, 4894–4901 (2006).

    PubMed  CAS  Google Scholar 

  • Salaun, B., Zitvogel, L., Asselin-Paturel, C., Morel, Y., Chemin, K., Dubois, C., Massacrier, C., Conforti, R., Chenard, M. P., Sabourin, J. C., Goubar, A., Lebecque, S., Pierres, M., Rimoldi, D., Romero, P., and Andre, F., TLR3 as a biomarker for the therapeutic efficacy of double-stranded RNA in breast cancer. Cancer Res., 71, 1607–1614 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Sato, M., Harada, K., Yoshida, H., Yura, Y., Azuma, M., Iga, H., Bando, T., Kawamata, H., and Takegawa, Y., Therapy for oral squamous cell carcinoma by tegafur and streptococcal agent OK-432 in combination with radiotherapy: association of the therapeutic effect with differentiation and apoptosis in the cancer cells. Apoptosis, 2, 227–238 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Scheel, B., Aulwurm, S., Probst, J., Stitz, L., Hoerr, I., Rammensee, H. G., Weller, M., and Pascolo, S., Therapeutic anti-tumor immunity triggered by injections of immunostimulating single-stranded RNA. Eur. J. Immunol., 36, 2807–2816 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Schmausser, B., Andrulis, M., Endrich, S., Muller-Hermelink, H. K., and Eck, M., 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 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Schnare, M., Barton, G. M., Holt, A. C., Takeda, K., Akira, S., and Medzhitov, R., Toll-like receptors control activation of adaptive immune responses. Nat. Immunol., 2, 947–950 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Schon, M. P. and Schon, M., TLR7 and TLR8 as targets in cancer therapy. Oncogene, 27, 190–199 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Sheyhidin, I., Nabi, G., Hasim, A., Zhang, R. P., Ainiwaer, J., Ma, H., and Wang, H., Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma. World J. Gastroenterol., 17, 3745–3751 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Shojaei, H., Oberg, H. H., Juricke, M., Marischen, L., Kunz, M., Mundhenke, C., Gieseler, F., Kabelitz, D., and Wesch, D., Toll-like receptors 3 and 7 agonists enhance tumor cell lysis by human gammadelta T cells. Cancer Res., 69, 8710–8717 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Simons, M. P., O’donnell, M. A., and Griffith, T. S., Role of neutrophils in BCG immunotherapy for bladder cancer. Urol. Oncol., 26, 341–345 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Song, C., Chen, L. Z., Zhang, R. H., Yu, X. J., and Zeng, Y. X., Functional variant in the 3′-untranslated region of Toll-like receptor 4 is associated with nasopharyngeal carcinoma risk. Cancer Biol. Ther., 5, 1285–1291 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Song, E. J., Kang, M. J., Kim, Y. S., Kim, S. M., Lee, S. E., Kim, C. H., Kim, D. J., and Park, J. H. Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5. Int. J. Mol. Med., 28, 115–119 (2011).

    PubMed  CAS  Google Scholar 

  • Spaner, D. E., Shi, Y., White, D., Shaha, S., He, L., Masellis, A., Wong, K., and Gorczynski, R., A phase I/II trial of TLR-7 agonist immunotherapy in chronic lymphocytic leukemia. Leukemia, 24, 222–226 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Sun, J., Wiklund, F., Zheng, S. L., Chang, B., Balter, K., Li, L., Johansson, J. E., Li, G., Adami, H. O., Liu, W., Tolin, A., Turner, A. R., Meyers, D. A., Isaacs, W. B., Xu, J., and Gronberg, H., Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J. Natl. Cancer Inst., 97, 525–532 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Szajnik, M., Szczepanski, M. J., Czystowska, M., Elishaev, E., Mandapathil, M., Nowak-Markwitz, E., Spaczynski, M., and Whiteside, T. L., TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene, 28, 4353–4363 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Szczepanski, M., Stelmachowska, M., Stryczynski, L., Golusinski, W., Samara, H., Mozer-Lisewska, I., and Zeromski, J., Assessment of expression of toll-like receptors 2, 3 and 4 in laryngeal carcinoma. Eur. Arch. Otorhinolaryngol., 264, 525–530 (2007).

    Article  PubMed  Google Scholar 

  • Szczepanski, M. J., Czystowska, M., Szajnik, M., Harasymczuk, M., Boyiadzis, M., Kruk-Zagajewska, A., Szyfter, W., Zeromski, J., and Whiteside, T. L., Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res., 69, 3105–3113 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Takeda, K. and Akira, S., TLR signaling pathways. Semin. Immunol., 16, 3–9 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Takeda, K., Kaisho, T., and Akira, S. Toll-like receptors. Annu. Rev. Immunol., 21, 335–376 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Tang, X. Y., Zhu, Y. Q., Wei, B., and Wang, H., Expression and functional research of TLR4 in human colon carcinoma. Am. J. Med. Sci., 339, 319–326 (2010).

    PubMed  Google Scholar 

  • Uenishi, Y., Kawabe, K., Nomura, T., Nakai, M., and Sunagawa, M., Morphological study on Mycobacterium bovis BCG Tokyo 172 cell wall skeleton (SMP-105). J. Microbiol. Methods, 77, 139–144 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Vollmer, J. and Krieg, A. M., Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv. Drug Deliv. Rev., 61, 195–204 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Wang, H., Rayburn, E. R., Wang, W., Kandimalla, E. R., Agrawal, S., and Zhang, R., Chemotherapy and chemosensitization of non-small cell lung cancer with a novel immunomodulatory oligonucleotide targeting Toll-like receptor 9. Mol. Cancer Ther., 5, 1585–1592 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Wang, J. H., Manning, B. J., Wu, Q. D., Blankson, S., Bouchier-Hayes, D., and Redmond, H. P., Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J. Immunol., 170, 795–804 (2003).

    PubMed  CAS  Google Scholar 

  • Xu, H., Wu, Q., Dang, S., Jin, M., Xu, J., Cheng, Y., Pan, M., Wu, Y., Zhang, C., and Zhang, Y., Alteration of CXCR7 Expression mediated by TLR4 promotes tumor cell proliferation and migration in human colorectal carcinoma. PLoS One, 6, e27399 (2011).

    Google Scholar 

  • Yang, H., Zhou, H., Feng, P., Zhou, X., Wen, H., Xie, X., Shen, H., and Zhu, X., Reduced expression of Toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion. J. Exp. Clin. Cancer Res., 29, 92 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Yoneda, K., Sugimoto, K., Shiraki, K., Tanaka, J., Beppu, T., Fuke, H., Yamamoto, N., Masuya, M., Horie, R., Uchida, K., and Takei, Y., Dual topology of functional Toll-like receptor 3 expression in human hepatocellular carcinoma: differential signaling mechanisms of TLR3-induced NFkappaB activation and apoptosis. Int. J. Oncol., 33, 929–936 (2008).

    PubMed  CAS  Google Scholar 

  • Yu, L. and Chen, S., Toll-like receptors expressed in tumor cells: targets for therapy. Cancer Immunol Immunother., 57, 1271–1278 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Yu, L., Wang, L., and Chen, S., Exogenous or endogenous Tolllike receptor ligands: which is the MVP in tumorigenesis? Cell. Mol. Life Sci., 69, 935–949 (2012).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, J. J., Wu, H. S., Wang, L., Tian, Y., Zhang, J. H., and Wu, H. L., Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma. World J. Gastroenterol., 16, 2881–2888 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Y., Sun, R., Liu, B., Deng, M., Zhang, W., Li, Y., Zhou, G., Xie, P., Li, G., and Hu, J., TLR3 activation inhibits nasopharyngeal carcinoma metastasis via downregulation of chemokine receptor CXCR4. Cancer Biol. Ther., 8, 1826–1830 (2009a).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Y. B., He, F. L., Fang, M., Hua, T. F., Hu, B. D., Zhang, Z. H., Cao, Q., and Liu, R. Y., Increased expression of Tolllike receptors 4 and 9 in human lung cancer. Mol. Biol. Rep., 36, 1475–1481 (2009b).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Z. and Schluesener, H. J., Mammalian toll-like receptors: from endogenous ligands to tissue regeneration. Cell. Mol. Life Sci., 63, 2901–2907 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Zheng, S. L., Augustsson-Balter, K., Chang, B., Hedelin, M., Li, L., Adami, H. O., Bensen, J., Li, G., Johnasson, J. E., Turner, A. R., Adams, T. S., Meyers, D. A., Isaacs, W. B., Xu, J., and Gronberg, H., 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 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Zhou, M., Mcfarland-Mancini, M. M., Funk, H. M., Husseinzadeh, N., Mounajjed, T., and Drew, A. F., Toll-like receptor expression in normal ovary and ovarian tumors. Cancer Immunol. Immunother., 58, 1375–1385 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Zhou, X. X., Jia, W. H., Shen, G. P., Qin, H. D., Yu, X. J., Chen, L. Z., Feng, Q. S., Shugart, Y. Y., and Zeng, Y. X., Sequence variants in toll-like receptor 10 are associated with nasopharyngeal carcinoma risk. Cancer Epidemiol. Biomarkers Prev., 15, 862–866 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Zhu, J., Brownlie, R., Liu, Q., Babiuk, L. A., Potter, A., and Mutwiri, G. K., Characterization of bovine Toll-like receptor 8: ligand specificity, signaling essential sites and dimerization. Mol. Immunol., 46, 978–990 (2009).

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea

    Shaherin Basith, Tae Hyeon Yoo & Sangdun Choi

  2. Center for In Silico Protein Science, School of Computational Sciences, Korea Institute for Advanced Study, Seoul, 130-722, Korea

    Balachandran Manavalan

  3. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Korea

    Sang Geon Kim

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Basith, S., Manavalan, B., Yoo, T.H. et al. Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense. Arch. Pharm. Res. 35, 1297–1316 (2012). https://doi.org/10.1007/s12272-012-0802-7

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