JCT  Vol.4 No.5 , July 2013
Toll-Like Receptors as Biomarkers of Gastric Carcinogenesis: Implications for Diagnosis, Prognosis and Treatment
ABSTRACT

Toll-like receptors (TLR) are essential for Helicobacter pylori (Hp) recognition and subsequent innate and adaptive immunity responses. TLR2 appears to be the receptor responsible for most of the immunologic reaction against Hp infection. However, TLR4, TLR9 and eventually TLR5 may also have a synergic effect with TLR2 against Hp. It has been shown that gastric Hp infection increases TLR expression in the gastric mucosa. Moreover, recent studies have shown that human gastric carcinogenesis is associated not only with increased expression of TLR but also with decreased expression of their inhibitors such as Toll-Interacting Protein (TOLLIP) and peroxisome proliferator-activated receptor (PPAR)-g. Indeed, gastric dysplasia and adenocarcinoma are associated with high expression levels of TLR and low levels of TOLLIP and PPAR-g, suggesting increased activation of these receptors throughout human gastric carcinogenesis. In this article we discuss how these novels findings could be used not only for the diagnosis and prognosis of gastric lesions associated with Hp infection but also for their treatment. Specifically, we discuss the potential use of TLR agonists in addition to antibiotics to improve eradication rates of Hp and of TLR antagonists to slow the progression of gastric preneoplastic lesions. We also discuss the potential value of TLR signalling blockers and quantification of tumoral TLR expression, respectively, in the treatment and prognosis of gastric cancer. In conclusion, TLRs can be an important link between Hp and the sequence of gastric carcinogenesis and they can be used as biomarkers of gastric carcinogenesis. In this article, future lines of investigation related with these novel scientific findings are proposed and discussed.


Cite this paper
P. Pimentel-Nunes, J. Soares and M. Dinis-Ribeiro, "Toll-Like Receptors as Biomarkers of Gastric Carcinogenesis: Implications for Diagnosis, Prognosis and Treatment," Journal of Cancer Therapy, Vol. 4 No. 5, 2013, pp. 1037-1047. doi: 10.4236/jct.2013.45117.
References
[1]   D. A. Pleura and S. E. Crowe. “Helicobacter pylori,” In: L. Feldman, L. Friedman and J. Brandt, Eds., Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Saun ders Elsevier, Philadelphia, 2010, pp. 833-843.

[2]   World Health Organization and International Agency for Research on Cancer, “Schistosomes, Liver Flukes and Helicobacter pylori,” IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon, 7-14 June 1994, pp. 1-241.

[3]   M. Clyne and B. Drumm, “Adherence of Helicobacter pylori to Primary Human Gastrointestinal Cells,” Infection and Immunity, Vol. 61, No. 10, 1993, pp. 4051-4057.

[4]   P. Pimentel-Nunes, J. B. Soares, R. Roncon-Albuquerque Jr., M. Dinis-Ribeiro and A. F. Leite-Moreira, “Toll-Like Receptors as Therapeutic Targets in Gastrointestinal Diseases,” Expert Opinion on Therapeutic Targets, Vol. 14, No. 4, 2010, pp. 347-368. doi:10.1517/14728221003642027

[5]   P. Laurèn, “The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma,” Acta Pathologica Microbiologica Scandinavica, Vol. 64, No. 1, 1965, pp. 31-49.

[6]   A. Fukao, S. Hisamichi, N. Ohsato, N. Fujino, N. Endo and M. Iha, “Correlation between the Prevalence of Gastritis and Gastric Cancer in Japan,” Cancer Causes Control, Vol. 4, No. 17, 1993, p. 20.

[7]   C. R. Kapadia, “Gastric Atrophy, Metaplasia and Dysplasia. A Clinical Perspective,” Journal of Clinical Gastroenterology, Vol. 36, No. 5, 2003, pp. S29-S36. doi:10.1097/00004836-200305001-00006

[8]   R. M. Genta, “Review Article: Gastric Atrophy and Atrophic Gastritis—Nebulous Concepts in Search of a Definition,” Alimentary Pharmacology & Therapeutics, Vol. 12, Supplement 1, 1998, pp. 17-23. doi:10.1111/j.1365-2036.1998.00003.x

[9]   P. Correa, “Human Gastric Carcinogenesis: A Multistep and Multifactorial Process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention,” Cancer Research, Vol. 52, No. 24, 1992, pp. 6735-6740.

[10]   P. B. Ernst and B. D. Gold, “The Disease Spectrum of Helicobacter pylori: The Immunopathogenesis of Gastroduodenal Ulcer and Gastric Cancer,” Annual Review of Microbiology, Vol. 54, No. 1, 2000, pp. 615-640. doi:10.1146/annurev.micro.54.1.615

[11]   T. Ihamaki, M. Sankkonen and M. Siurala, “Long Term Observation of Subjects with Normal Mucosa and with Superficial Gastritis: Results of 23-27 Years Follow-Up Examination,” Scandinavian Journal of Gastroenterology, Vol. 13, No. 7, 1978, pp. 771-775. doi:10.3109/00365527809182189

[12]   M. C. Ormiston, M. W. Gear and B. W. Codling, “Five Year Follow-Up Study of Gastritis,” Journal of Clinical Pathology, Vol. 35, No. 7, 1982, pp. 757-760. doi:10.1136/jcp.35.7.757

[13]   S. Akira and H. Hemmi, “Recognition of Pathogen-Associated Molecular Patterns by TLR Family,” Immunology Letters, Vol. 85, No. 2, 2003, pp. 85-95. doi:10.1016/S0165-2478(02)00228-6

[14]   K. Takeda, T. Kaisho and S. Akira, “Toll-Like Receptors,” Annual Review of Immunology, Vol. 21, No. 1, 2003, pp. 335-376. doi:10.1146/annurev.immunol.21.120601.141126

[15]   G. M. Barton and R. Medzhitov, “Control of Adaptive Immune Responses by Toll-Like Receptors,” Current Opinion in Immunology, Vol. 14, No. 3, 2002, pp. 380-383. doi:10.1016/S0952-7915(02)00343-6

[16]   G. Napolitani, A. Rinaldi, F. Bertoni, F. Sallusto and A. Lanzavecchia, “Selected Toll-Like Receptor Agonist Combinations Synergistically Trigger A T Helper Type 1-Polarizing Program in Dendritic Cells,” Nature Immunology, Vol. 6, No. 8, 2005, pp. 769-776. doi:10.1038/ni1223

[17]   S. Akira and K. Takeda, “Toll-Like Receptor Signaling,” Nature Reviews Immunology, Vol. 4, No. 7, 2004, pp. 499-511. doi:10.1038/nri1391

[18]   T. Kawai and S. Akira, “TLR Signaling,” Cell Death & Differentiation, Vol. 13, No. 5, 2006, pp. 816-825. doi:10.1038/sj.cdd.4401850

[19]   F. L. Rock, G. Hardiman, J. C. Timans, R. A. Kastelein and J. F. Bazan, “A Family of Human Receptors Structurally Related to Drosophila Toll,” Proceedings of the National Academy of Sciences of the United States of America Vol. 95, No. 2, 1998, pp. 588-593. doi:10.1073/pnas.95.2.588

[20]   P. A. Hopkins and S. Sriskandan, “Mammalian Toll-Like Receptors: To Immunity and Beyond,” Clinical & Experimental Immunology, Vol. 140, No. 3, 2005, pp. 395-407. doi:10.1111/j.1365-2249.2005.02801.x

[21]   H. Kumar, T. Kawai and S. Akira, “Toll-Like Receptors and Innate Immunity,” Biochemical and Biophysical Research Communications Vol. 388, No. 4, 2009, pp. 621-625. doi:10.1016/j.bbrc.2009.08.062

[22]   S. Akira, S. Uematsu and O. Takeuchi, “Pathogen Recognition and Innate Immunity,” Cell, Vol. 124, No. 4, 2006, pp. 783-801. doi:10.1016/j.cell.2006.02.015

[23]   B. Beutler, “Neo-Ligands for Innate Immune Receptors and the Etiology of Sterile Inflammatory Disease,” Immunological Reviews, Vol. 220, No. 1, 2007, pp. 113-128. doi:10.1111/j.1600-065X.2007.00577.x

[24]   M. T. Lotze, H. J. Zeh, A. Rubartelli, L. J. Sparvero, A. A. Amoscato, N. R. Washburn, M. E. Devera, X. Liang, M. Tor and T. Billiar, “The Grateful Dead: Damage-Associated Molecular Pattern Molecules and Reduction/Oxidation Regulate Immunity,” Immunological Reviews, Vol. 220, No. 1, 2007, pp. 60-81. doi:10.1111/j.1600-065X.2007.00579.x

[25]   T. Kaisho and S. Akira, “Pleiotropic Function of TollLike Receptors,” Microbes and Infection, Vol. 6, No. 15, 2004, pp. 1388-1394. doi:10.1016/j.micinf.2004.08.019

[26]   M. Fukata, A. Chen, A. Klepper, S. Krishnareddy, A. S. Vamadevan, L. S. Thomas, R. Xu, H. Inoue, M. Arditi, A. J. Dannenberg, et al., “Cox-2 is Regulated by Toll-Like Receptor-4 (TLR4) Signaling: Role in Proliferation and Apoptosis in the Intestine,” Gastroenterology, Vol. 131, No. 3, 2006, pp. 862-877. doi:10.1016/j.micinf.2004.08.019

[27]   Y. J. Chang, M. S. Wu, J. T. Lin and C. C. Chen, “Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation,” The Journal of Immunology, Vol. 175, No. 12, 2005, pp. 8242-8252.

[28]   J. A. Spitzer, M. Zheng, J. K. Kolls, C. Vande Stouwe and J. J. Spitzer, “Ethanol and LPS Modulate NF-KappaB Activation, Inducible NO Synthase and COX-2 Gene Expression in Rat Liver Cells in Vivo,” Frontiers in Bioscience, Vol. 7, 2002, pp. a99-a108. doi:10.2741/spitzer

[29]   I. T. Lee, C. W. Lee, W. H. Tung, S. W. Wang, C. C. Lin, J. C. Shu and C. M. Yang, “Cooperation of TLR2 with MyD88, PI3K, and Rac1 in Lipoteichoic Acid-Induced cPLA2/CO X-2-Dependent Airway Inflammatory Responses,” American Journal of Pathology, Vol. 176, No. 4, 2010, pp. 1671-1684. doi:10.2353/ajpath.2010.090714

[30]   M. Palazzo, S. Gariboldi, L. Zanobbio, G. F. Dusio, S. Selleri, M. Bedoni, A. Balsari and C. Rumio, “Cross-Talk among Toll-Like Receptors and Their Ligands,” International Immunology, Vol. 20, No. 5, 2008, pp. 709-718. doi:10.1093/intimm/dxn027

[31]   F. Re and J. L. Strominger, “IL-10 Released by Concomitant TLR2 Stimulation Blocks the Induction of a Subset of Th1 Cytokines That Are Specifically Induced by TLR4 or TLR3 in Human Dendritic Cells,” The Journal of Immunology, Vol. 173, No. 12, 2004, pp. 7548-7555.

[32]   F. Re and J. L. Strominger, “Heterogeneity of TLR-Induced Responses in Dendritic Cells: From Innate to Adaptive Immunity,” Immunobiology, Vol. 209, No. 1-2, 2004, pp. 191-198. doi:10.1016/j.imbio.2004.03.005

[33]   M. Fukata and M. T. Abreu, “Role of Toll-Like Receptors in Gastrointestinal Malignancies,” Oncogene, Vol. 27, No. 2, 2008, pp. 234-243. doi:10.1038/sj.onc.1210908

[34]   M. Fukata and M. T. Abreu, “Pathogen Recognition Receptors, Cancer and Inflammation in the Gut,” Current Opinion in Pharmacology, Vol. 9, No. 6, 2009, pp. 680-687. doi:10.1016/j.coph.2009.09.006

[35]   P. Desreumaux, L. Dubuquoy, S. Nutten, M. Peuchmaur, W. Englaro, K. Schoonjans, B. Derijard, B. Desvergne, W. Wahli, P. Chambon, et al., “Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (RXR)/Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma) Heterodimer. A Basis for New Therapeutic Strategies,” The Journal of Experimental Medicine, Vol. 193, No. 7, 2001, pp. 827-838. doi:10.1084/jem.193.7.827

[36]   R. A. Gupta, D. B. Polk, U. Krishna, D. A. Israel, F. Yan, R. N. DuBois and R. M. Peek Jr., “Activation of Peroxisome Proliferator-Activated Receptor Gamma Suppresses Nuclear Factor Kappa B-Mediated Apoptosis Induced by Helicobacter pylori in Gastric Epithelial Cells,” The Journal of Biological Chemistry, Vol. 276, No. 33, 2001, pp. 31059-31066. doi:10.1074/jbc.M104141200

[37]   D. Kelly, J. I. Campbell, T. P. King, G. Grant, E. A. Jansson, A. G. Coutts, S. Pettersson and S. Conway, “Commensal Anaerobic Gut Bacteria Attenuate Inflammation by Regulating Nuclear-Cytoplasmic Shuttling of PPARGamma and RelA,” Nature Immunology, Vol. 5, No. 1, 2004, pp. 104-112.

[38]   G. Melmed, L. S. Thomas, N. Lee, S. Y. Tesfay, K. Lukasek, K. S. Michelsen, Y. Zhou, B. Hu, M. Arditi and M. T. Abreu, “Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut,” Journal of Immunology, Vol. 170, No. 3, 2003, pp. 1406-1415.

[39]   J. M. Otte, E. Cario and D. K. Podolsky, “Mechanisms of Cross Hyporesponsiveness to Toll-Like Receptor Bacterial Ligands in Intestinal Epithelial Cells,” Gastroenterology, Vol. 126, No. 4, 2004, pp. 1054-1070. doi:10.1053/j.gastro.2004.01.007

[40]   F. Y. Liew, D. Xu, E. K. Brint and L. A. O’Neill, “Negative Regulation of Toll-Like Receptor-Mediated Immune Responses,” Nature Reviews Immunology, Vol. 5, No. 6, 2005, pp. 446-458.

[41]   C. F. Ortega-Cava, S. Ishihara, M. A. Rumi, K. Kawashima, N. Ishimura, H. Kazumori, J. Udagawa, Y. Kadowaki and Y. Kinoshita, “Strategic Compartmentalization of Toll-Like Receptor 4 in the Mouse Gut,” Journal of Immunology, Vol. 170, No. 8, 2003, pp. 3977-3985.

[42]   M. T. Abreu, L. S. Thomas, E. T. Arnold, K. Lukasek, K. S. Michelsen and M. Arditi, “TLR Signaling at the Intestinal Epithelial Interface,” Journal of Endotoxin Research, Vol. 9, No. 5, 2003, pp. 322-330.

[43]   M. T. Abreu, P. Vora, E. Faure, L. S. Thomas, E. T. Arnold and M. Arditi, “Decreased Expression of Toll-Like Receptor-4 and MD-2 Correlates with Intestinal Epithelial Cell Protection against Dysregulated Proinflammatory Gene Expression in Response to Bacterial Lipopolysaccharide,” Journal of Immunology, Vol. 167, No. 3, 2001, pp. 1609-1616.

[44]   E. Furrie, S. Macfarlane, G. Thomson and G. T. Macfarlane, “Toll-Like Receptors-2, -3 and -4 Expression Patterns on Human Colon and Their Regulation by Mucosal-Associated Bacteria,” Immunology, Vol. 115, No. 4, 2005, pp. 565-574. doi:10.1111/j.1365-2567.2005.02200.x

[45]   T. H. Chuang and R. J. Ulevitch, “Triad3A, an E3 Ubiquitin-Protein Ligase Regulating Toll-Like Receptors,” Nature Immunology, Vol. 5, No. 5, 2004, pp. 495-502. doi:10.1038/ni1066

[46]   A. Mansell, R. Smith, S. L. Doyle, P. Gray, J. E. Fenner, P. J. Crack, S. E. Nicholson, D. J. Hilton, L. A. O’Neill and P. J. Hertzog, “Suppressor of Cytokine Signaling 1 Negatively Regulates Toll-Like Receptor Signaling by Mediating Mal Degradation,” Nature Immunology, Vol. 7, No. 2, 2006, pp. 148-155.

[47]   R. Rad, L. Brenner, A. Krug, P. Voland, J. Mages, R. Lang, S. Schwendy, W. Reindl, A. Dossumbekova, W. Ballhorn, et al., “Toll-Like Receptor-Dependent Activation of Antigen-Presenting Cells Affects Adaptive Immunity to Helicobacter pylori,” Gastroenterology, Vol. 133, No. 1, 2007, pp. 150-163.

[48]   R. Takenaka, K. Yokota, K. Ayada, M. Mizuno, Y. Zhao, Y. Fujinami, S. N. Lin, T. Toyokawa, H. Okada, Y. Shiratori, et al., “Helicobacter pylori Heat-Shock Protein 60 Induces Inflammatory Responses through the Toll-Like Receptor-Triggered Pathway in Cultured Human Gastric Epithelial Cells,” Microbiology, Vol. 150, No. 12, 2004, pp. 3913-3922. doi:10.1099/mic.0.27527-0

[49]   R. Rad, W. Ballhorn, P. Voland, K. Eisenacher, J. Mages, L. Rad, R. Ferstl, R. Lang, H. Wagner, R. M. Schmid, et al., “Extracellular and Intracellular Pattern Recognition Receptors Cooperate in the Recognition of Helicobacter pylori,” Gastroenterology, Vol. 136, No. 7, 2009, pp. 2247-2257. doi:10.1053/j.gastro.2009.02.066

[50]   K. Uno, K. Kato, T. Atsumi, T. Suzuki, J. Yoshitake, H. Morita, S. Ohara, Y. Kotake, T. Shimosegawa and T. Yoshimura, “Toll-Like Receptor (TLR) 2 Induced through TLR4 Signaling Initiated by Helicobacter pylori Cooperatively Amplifies iNOS Induction in Gastric Epithelial Cells,” American Journal of Physiology Gastrointestinal and Liver Physiology, Vol. 293, No. 5, 2007, pp. G1004-G1012. doi:10.1152/ajpgi.00096.2007

[51]   M. Obonyo, M. Sabet, S. P. Cole, J. Ebmeyer, S. Uematsu, S. Akira and D. G. Guiney, “Deficiencies of Myeloid Differentiation Factor 88, Toll-Like Receptor 2 (TLR2), or TLR4 Produce Specific Defects in Macrophage Cytokine Secretion Induced by Helicobacter pylori,” Infection and Immunity, Vol. 75, No. 5, 2007, pp. 2408-2414. doi:10.1128/IAI.01794-06

[52]   A. P. Gobert, J. C. Bambou, C. Werts, V. Balloy, M. Chignard, A. P. Moran and R. L. Ferrero, “Helicobacter pylori Heat Shock Protein 60 Mediates Interleukin-6 Production by Macrophages via a Toll-Like Receptor (TLR)-2-, TLR-4-, and Myeloid Differentiation Factor 88-Independent Mechanism. The Journal of Biological Chemistry, Vol. 279, No. 1, 2004, pp. 245-250. doi:10.1074/jbc.M307858200

[53]   S. K. Lee, A. Stack, E. Katzowitsch, S. I. Aizawa, S. Suerbaum and C. Josenhans, “Helicobacter pylori Flagellins Have very Low Intrinsic Activity to Stimulate Human Gastric Epithelial Cells via TLR5,” Microbes and Infection, Vol. 5, No. 15, 2003, pp. 1345-1356. doi:10.1016/j.micinf.2003.09.018

[54]   E. Andersen-Nissen, K. D. Smith, K. L. Strobe, S. L. Barrett, B. T. Cookson, S. M. Logan and A. Aderem, “Evasion of Toll-Like Receptor 5 by Flagellated Bacteria,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 26, 2005, pp. 9247-9252. doi:10.1073/pnas.0502040102

[55]   A. T. Gewirtz, Y. Yu, U. S. Krishna, D. A. Israel, S. L. Lyons and R. M. Peek Jr., “Helicobacter pylori Flagellin Evades Toll-Like Receptor 5-Mediated Innate Immunity,” The Journal of Infectious Diseases, Vol. 189, No. 10, 2004, pp. 1914-1920. doi:10.1086/386289

[56]   M. F. Smith Jr., A. Mitchell, G. Li, S. Ding, A. M. Fitzmaurice, K. Ryan, S. Crowe and J. B. Goldberg, “Toll-Like Receptor (TLR) 2 and TLR5, but Not TLR4, Are Required for Helicobacter pylori-Induced NF-kappa B Activation and Chemokine Expression by Epithelial Cells,” The Journal of Biological Chemistry, Vol. 278, No. 35, 2003, pp. 32552-32560. doi:10.1074/jbc.M305536200

[57]   A. Amedei, A. Cappon, G. Codolo, A. Cabrelle, A. Polenghi, M. Benagiano, E. Tasca, A. Azzurri, M. M. D’Elios, G. Del Prete, et al., “The Neutrophil-Activating Protein of Helicobacter pylori Promotes Th1 Immune Responses,” The Journal of Clinical Investigation, Vol. 116, No. 4, 2006, pp. 1092-1101. doi:10.1172/JCI27177

[58]   L. Mandell, A. P. Moran, A. Cocchiarella, J. Houghton, N. Taylor, J. G. Fox, T. C. Wang and E. A. Kurt-Jones, “Intact Gram-Negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus Bacteria Activate Innate Immunity via Toll-Like Receptor 2 but Not Toll-Like Receptor 4,” Infection and Immunity, Vol. 72, No. 11, 2004, pp. 6446-6454. doi:10.1128/IAI.72.11.6446-6454.2004

[59]   C. Basak, S. K. Pathak, A. Bhattacharyya, S. Pathak, J. Basu and M. Kundu, “The Secreted Peptidyl Prolyl Cis, Trans-Isomerase HP0175 of Helicobacter pylori Induces Apoptosis of Gastric Epithelial Cells in a TLR4-and Apoptosis Signal-Regulating Kinase 1-Dependent Manner,” Journal of Immunology, Vol. 174, No. 9, 2005, pp. 5672-5680.

[60]   S. Ishihara, M. A. Rumi, Y. Kadowaki, C. F. Ortega-Cava, T. Yuki, N. Yoshino, Y. Miyaoka, H. Kazumori, N. Ishimura, Y. Amano, et al., “Essential Role of MD-2 in TLR4-Dependent Signaling during Helicobacter pyloriAssociated Gastritis,” Journal of Immunology, Vol. 173, No. 2, 2004, pp. 1406-1416.

[61]   T. Kawahara, Y. Kuwano, S. Teshima-Kondo, T. Kawai, T. Nikawa, K. Kishi and K. Rokutan, “Toll-Like Receptor 4 Regulates Gastric Pit Cell Responses to Helicobacter pylori Infection,” The Journal of Medical Investigation, Vol. 48, No. 3-4, 2001, pp. 190-197.

[62]   A. M. Torok, A. H. Bouton and J. B. Goldberg, “Helicobacter pylori Induces Interleukin-8 Secretion by TollLike Receptor 2-and Toll-Like Receptor 5-Dependent and -Independent Pathways,” Infection and Immunity, Vol. 73, No. 3, 2005, pp. 1523-1531. doi:10.1128/IAI.73.3.1523-1531.2005

[63]   S. K. Pachathundikandi, S. Brandt, J. Madassery and S. Backert, “Induction of TLR-2 and TLR-5 Expression by Helicobacter pylori Switches cagPAI-Dependent Signalling Leading to the Secretion of IL-8 and TNF-Alpha,” PloS One, Vol. 6, No. 5, 2011, p. e19614. doi:10.1371/journal.pone.0019614

[64]   A. E. Anderson, M. L. Worku, W. Khamri, K. B. Bamford, M. M. Walker and M. R. Thursz, “TLR9 Polymorphisms Determine Murine Lymphocyte Responses to Helicobacter: Results from a Genome-Wide Scan,” European Journal of Immunology, Vol. 37, No. 6, 2007, pp. 1548-1561. doi:10.1002/eji.200636562

[65]   P. Pimentel-Nunes, L. Afonso, P. Lopes, R. RonconAlbuquerque Jr., N. Goncalves, R. Henrique, L. MoreiraDias, A. F. Leite-Moreira and M. Dinis-Ribeiro, “Increased Expression of Toll-like Receptors (TLR) 2, 4 and 5 in Gastric Dysplasia,” Pathology & Oncology Research, Vol. 17, No. 3, 2011, pp. 677-683. doi:10.1007/s12253-011-9368-9

[66]   B. Schmausser, M. Andrulis, S. Endrich, H. K. MullerHermelink and M. Eck, “Toll-Like Receptors TLR4, TLR5 and TLR9 on Gastric Carcinoma Cells: An Implication for Interaction with Helicobacter pylori,” International Journal of Medical Microbiology, Vol. 295, No. 3, 2005, pp. 179-185. doi:10.1016/j.ijmm.2005.02.009

[67]   P. Pimentel-Nunes, N. Goncalves, I. Boal-Carvalho, L. Afonso, P. Lopes, R. Roncon-Albuquerque Jr., R. Henrique, L. Moreira-Dias, A. F. Leite-Moreira and M. DinisRibeiro, “Helicobacter pylori Induces Increased Expression of Toll-Like Receptors and Decreased Toll-Interacting Protein in Gastric Mucosa that Persists throughout Gastric Carcinogenesis,” Helicobacter, Vol. 18, No. 1, 2013, pp. 22-32.

[68]   P. Pimentel-Nunes, N. Goncalves, I. Boal-Carvalho, L. Afonso, P. Lopes, R. Roncon-Albuquerque Jr., J. B. Soares, E. Cardoso, R. Henrique, L. Moreira-Dias, et al., “Decreased Toll-Interacting Protein and Peroxisome Proliferator-Activated Receptor Gamma Are Associated with Increased Expression of Toll-Like Receptors in Colon Carcinogenesis,” Journal of Clinical Pathology, Vol. 65, No. 4, 2012, pp. 302-308. doi:10.1136/jclinpath-2011-200567

[69]   Y. Bulut, E. Faure, L. Thomas, O. Equils and M. Arditi, “Cooperation of Toll-Like Receptor 2 and 6 for Cellular Activation by Soluble Tuberculosis Factor and Borrelia burgdorferi Outer Surface Protein A Lipoprotein: Role of Toll-Interacting Protein and IL-1 Receptor Signaling Molecules in Toll-Like Receptor 2 Signaling,” Journal of Immunology, Vol. 167, No. 2, 2001, pp. 987-994.

[70]   G. Zhang and S. Ghosh, “Negative Regulation of TollLike Receptor-Mediated Signaling by Tollip,” The Journal of Biological Chemistry, Vol. 277, No. 9, 2002, pp. 7059-7065. doi:10.1074/jbc.M109537200

[71]   B. Brissoni, L. Agostini, M. Kropf, F. Martinon, V. Swoboda, S. Lippens, H. Everett, N. Aebi, S. Janssens, E. Meylan, et al., “Intracellular Trafficking of Interleukin-1 Receptor I Requires Tollip,” Current Biology, Vol. 16, No. 22, 2006, pp. 2265-2270. doi:10.1016/j.cub.2006.09.062

[72]   A. Didierlaurent, B. Brissoni, D. Velin, N. Aebi, A. Tardivel, E. Kaslin, J. C. Sirard, G. Angelov, J. Tschopp and K. Burns, “Tollip Regulates Proinflammatory Responses to Interleukin-1 and Lipopolysaccharide,” Molecular and Cellular Biology, Vol. 26, No. 3, 2006, pp. 735-742. doi:10.1128/MCB.26.3.735-742.2006

[73]   Y. Katoh, H. Imakagura, M. Futatsumori and K. Nakayama, “Recruitment of Clathrin onto Endosomes by the Tom1-Tollip Complex,” Biochemical and Biophysical Research, Vol. 341, No. 1, 2006, pp. 143-149. doi:10.1016/j.bbrc.2005.12.156

[74]   Y. Katoh, Y. Shiba, H. Mitsuhashi, Y. Yanagida, H. Takatsu and K. Nakayama, “Tollip and Tom1 Form a Complex and Recruit Ubiquitin-Conjugated Proteins onto Early Endosomes,” The Journal of Biological Chemistry, Vol. 279, No. 23, 2004, pp. 24435-24443. doi:10.1074/jbc.M400059200

[75]   H. Ikeda, M. Sasaki, A. Ishikawa, Y. Sato, K. Harada, Y. Zen, H. Kazumori and Y. Nakanuma, “Interaction of Toll-Like Receptors with Bacterial Components Induces Expression of CDX2 and MUC2 in Rat Biliary Epithelium in Vivo and in Culture,” Laboratory Investigation, Vol. 87, No. 6, 2007, pp. 559-571.

[76]   X. S. Feng, Y. F. Wang, S. G. Hao, Y. Ru, S. G. Gao and L. D. Wang, “Expression of CDX2 and Villin in Gastric Cardiac Intestinal Metaplasia and the Relation with Gastric Cardiac Carcinogenesis,” Asian Pacific Journal of Cancer Prevention, Vol. 13, No. 1, 2012, pp. 247-250. doi:10.7314/APJCP.2012.13.1.247

[77]   J. M. Kang, B. H. Lee, N. Kim, H. S. Lee, H. E. Lee, J. H. Park, J. S. Kim, H. C. Jung and I. S. Song, “CDX1 and CDX2 Expression in Intestinal Metaplasia, Dysplasia and Gastric Cancer,” Journal of Korean Medical Science, Vol. 26, No. 5, 2011, pp. 647-653. doi:10.3346/jkms.2011.26.5.647

[78]   R. M. Strieter, “Chemokines: Not Just Leukocyte Chemoattractants in the Promotion of Cancer,” Nature Immunology, Vol. 2, No. 4, 2001, pp. 285-286. doi:10.1038/86286

[79]   K. Chochi, T. Ichikura, M. Kinoshita, T. Majima, N. Shinomiya, H. Tsujimoto, T. Kawabata, H. Sugasawa, S. Ono, S. Seki, et al., “Helicobacter pylori Augments Growth of Gastric Cancers via the Lipopolysaccharide-TollLike Receptor 4 Pathway whereas Its Lipopolysaccharide Attenuates Antitumor Activities of Human Mononuclear Cells,” Clinical Cancer Research, Vol. 14, No. 10, 2008, pp. 2909-2917. doi:10.1158/1078-0432.CCR-07-4467

[80]   Y. J. Chang, M. S. Wu, J. T. Lin, B. S. Sheu, T. Muta, H. Inoue and C. C. Chen, “Induction of Cyclooxygenase-2 Overexpression in Human Gastric Epithelial Cells by Helicobacter pylori Involves TLR2/TLR9 and c-SrcDependent Nuclear Factor-KappaB Activation,” Molecular Pharmacology, Vol. 66, No. 6, 2004, pp. 1465-1477. doi:10.1124/mol.104.005199

[81]   B. Huang, J. Zhao, S. Shen, H. Li, K. L. He, G. X. Shen, L. Mayer, J. Unkeless, D. Li, Y. Yuan, et al., “Listeria monocytogenes Promotes Tumor Growth via Tumor Cell Toll-Like Receptor 2 Signaling,” Cancer Research, Vol. 67, No. 9, 2007, pp. 4346-4352. doi:10.1158/0008-5472.CAN-06-4067

[82]   J. G. de Oliveira, A. F. Rossi, D. M. Nizato, K. Miyasaki and A. E. Silva, “Profiles of Gene Polymorphisms in Cytokines and Toll-Like Receptors with Higher Risk for Gastric Cancer,” Digestive Diseases and Sciences, Vol. 58, No. 4, 2012, pp. 978-988.

[83]   D. Santini, S. Angeletti, A. Ruzzo, G. Dicuonzo, S. Galluzzo, B. Vincenzi, A. Calvieri, F. Pizzagalli, N. Graziano, E. Ferraro, et al., “Toll-Like Receptor 4 Asp299Gly and Thr399Ile Polymorphisms in Gastric Cancer of Intestinal and Diffuse Histotypes,” Clinical & Experimental Immunology, Vol. 154, No. 3, 2008, pp. 360-364. doi:10.1111/j.1365-2249.2008.03776.x

[84]   G. L. Hold, C. S. Rabkin, W. H. Chow, M. G. Smith, M. D. Gammon, H. A. Risch, T. L. Vaughan, K. E. McColl, J. Lissowska, W. Zatonski, et al., “A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors,” Gastroenterology, Vol. 132, No. 3, 2007, pp. 905-912. doi:10.1053/j.gastro.2006.12.026

[85]   T. Tahara, T. Arisawa, F. Wang, T. Shibata, M. Nakamura, M. Sakata, I. Hirata and H. Nakano, “Toll-Like Receptor 2 -196 to 174del Polymorphism Influences the Susceptibility of Japanese People to Gastric Cancer,” Cancer Science, Vol. 98, No. 11, 2007, pp. 1790-1794. doi:10.1111/j.1349-7006.2007.00590.x

[86]   H. M. Zeng, K. F. Pan, Y. Zhang, L. Zhang, J. L. Ma, T. Zhou, H. J. Su, W. Q. Li, J. Y. Li, M. Gerhard, et al., “Genetic Variants of Toll-Like Receptor 2 and 5, Helicobacter pylori Infection, and Risk of Gastric Cancer and Its Precursors in a Chinese Population,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 20, No. 12, 2011, pp. 2594-2602.

[87]   M. Dinis-Ribeiro, M. Areia, A. C. de Vries, R. Marcos-Pinto, M. Monteiro-Soares, A. O’Connor, C. Pereira, P. Pimentel-Nunes, R. Correia, A. Ensari, et al., “Management of Precancerous Conditions and Lesions in the Stomach (MAPS): Guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED),” Endoscopy, Vol. 44, No. 1, 2012, pp. 74-94. doi:10.1055/s-0031-1291491

[88]   P. Pimentel-Nunes, M. Dinis-Ribeiro, J. B. Soares, R. Marcos-Pinto, C. Santos, C. Rolanda, R. P. Bastos, M. Areia, L. Afonso, J. Bergman, et al., “A Multicenter Validation of an Endoscopic Classification with Narrow Band Imaging for Gastric Precancerous and Cancerous Lesions,” Endoscopy, Vol. 44, No. 3, 2012, pp. 236-246. doi:10.1055/s-0031-1291537

[89]   E. L. Wang, Z. R. Qian, M. Nakasono, T. Tanahashi, K. Yoshimoto, Y. Bando, E. Kudo, M. Shimada and T. Sano, “High Expression of Toll-Like Receptor 4/Myeloid Differentiation Factor 88 Signals Correlates with Poor Prognosis in Colorectal Cancer,” British Journal of Cancer Vol. 102, No. 5, 2010, pp. 908-915. doi:10.1038/sj.bjc.6605558

[90]   M. L. Slattery, J. S. Herrick, K. L. Bondurant and R. K. Wolff, “Toll-Like Receptor Genes and Their Association with Colon and Rectal Cancer Development and Prognosis,” International Journal of Cancer, Vol. 130, No. 12, 2012, pp. 2974-2980.

[91]   J. H. Kauppila, H. Takala, K. S. Selander, P. P. Lehenkari, J. Saarnio and T. J. Karttunen, “Increased Toll-Like Receptor 9 Expression Indicates Adverse Prognosis in Oesophageal Adenocarcinoma,” Histopathology, Vol. 59, No. 4, 2011, pp. 643-649. doi:10.1111/j.1365-2559.2011.03991.x

[92]   L. Moise, S. F. Moss and A. S. De Groot, “Moving Helicobacter pylori Vaccine Development Forward with Bioinformatics and Immunomics,” Expert Review of Vaccines, Vol. 11, No. 9, 2012, pp. 1031-1033. doi:10.1586/erv.12.80

[93]   P. Malfertheiner, V. Schultze, B. Rosenkranz, S. H. Kaufmann, T. Ulrichs, D. Novicki, F. Norelli, M. Contorni, S. Peppoloni, D. Berti, et al., “Safety and Immunogenicity of an Intramuscular Helicobacter pylori Vaccine in Noninfected Volunteers: A Phase I Study,” Gastroenterology, Vol. 135, No. 3, 2008, pp. 787-795. doi:10.1053/j.gastro.2008.05.054

[94]   K. Otani, T. Tanigawa, T. Watanabe, Y. Nadatani, M. Sogawa, H. Yamagami, M. Shiba, K. Watanabe, K. Tominaga, Y. Fujiwara, et al., “Toll-Like Receptor 9 Signaling Has Anti-Inflammatory Effects on the Early Phase of Helicobacter pylori-Induced Gastritis,” Biochemical and Biophysical Research Communications, Vol. 426, No. 3, 2012, pp. 342-349. doi:10.1016/j.bbrc.2012.08.080

 
 
Top