Top

Published in:

01-09-2011 | Research

Increased Expression of Toll-like Receptors (TLR) 2, 4 and 5 in Gastric Dysplasia

Authors: Pedro Pimentel-Nunes, Luís Afonso, Paula Lopes, Roberto Roncon-Albuquerque Jr, Nádia Gonçalves, Rui Henrique, Luís Moreira-Dias, Adelino F. Leite-Moreira, Mário Dinis-Ribeiro

Published in: Pathology & Oncology Research | Issue 3/2011

Abstract

TLRs are important innate immunity receptors. Even though TLR2, 4 and 5 appear to be important for Helicobacter pylori (HP) recognition, their role in the evolution of gastritis to more advanced lesions is still unknown. To compare the expression of TLR2, 4 and 5 in normal gastric mucosa, HP+ gastritis, intestinal metaplasia, dysplasia and adenocarcinoma. Immunohistochemistry for TLR2, 4 and 5 was performed with anti-TLR2-TLR4-TLR5 antibodies in 117 histological samples of normal gastric mucosa (n = 22), HP+ gastritis (n = 20), intestinal metaplasia (n = 33), dysplasia (mucosectomy specimens, n = 20) and intestinal type adenocarcinoma (surgery specimens,n = 22); quantification of expression was performed independently by two pathologists taking into account the percentage of positive epithelial cells and the degree of expression (zero to three score). A statistically significant trend for progressive increase of TLRs expression from normal mucosa to gastric dysplasia was found (mean expression: normal mucosa 0.1; gastritis 1.0; metaplasia 2.2; dysplasia 2.8, p < 0.01). All dysplasia samples presented more than 90% positive epithelial cells with strong expression (2.8;95%CI2.7–3). There was less TLRs expression in carcinomas (TLR2:1.0; TLR4:2.0 and TLR5:1.2, p < 0.05) when compared with dysplasia, with TLR4 being more expressed than TLR2 and 5 in these lesions (p = 0.03). A score of all markers’ expression of eight leads to a low (4%) false positive rate in patients with precancerous conditions. Progression of gastric lesions associated with gastric carcinogenesis is associated with increased TLRs expression. Gastric dysplasia presents a high level of TLRs expression, suggesting that these receptors may play a role in adenocarcinoma development.

Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95PubMedCrossRef

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

Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511. doi:10.1038/nri1391 PubMedCrossRef

Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825. doi:10.1038/sj.cdd.4401850 PubMedCrossRef

Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (1998) A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 95:588–593PubMedCrossRef

Medzhitov R, Janeway C Jr (2000) Innate immunity. N Engl J Med 343:338–344PubMedCrossRef

O’Mahony DS, Pham U, Iyer R, Hawn TR, Liles WC (2008) Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages. Int J Med Sci 5:1–8PubMed

Kaisho T, Akira S (2004) Pleiotropic function of Toll-like receptors. Microbes Infect 6:1388–1394. doi:10.1016/j.micinf.2004.08.019 PubMedCrossRef

Clyne M, Drumm B (1993) Adherence of Helicobacter pylori to primary human gastrointestinal cells. Infect Immun 61:4051–4057PubMed

10.

Ernst PB, Gold BD (2000) The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer. Annu Rev Microbiol 54:615–640PubMedCrossRef

11.

Fuchs CS, Mayer RJ (1995) Gastric carcinoma. N Engl J Med 333:32–41PubMedCrossRef

12.

Houghton J, Wang TC (2006) Tumors of the stomach. In: Feldman M, Friedman LS, Brandt LJ (eds) Sleisenger and Fordtran’s gastrointestinal and liver disease, 8 edn. Saunders Elsevier, pp 1139–1170

13.

Kuipers EJ, Perez-Perez GI, Meuwissen SG, Blaser MJ (1995) Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst 87:1777–1780PubMedCrossRef

14.

Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52:6735–6740PubMed

15.

Correa P (1995) Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 19(Suppl 1):S37–S43PubMed

16.

de Vries AC, Kuipers EJ, Rauws EA (2009) Helicobacter pylori eradication and gastric cancer: when is the horse out of the barn? Am J Gastroenterol 104:1342–1345. doi:10.1038/ajg.2008.15 PubMedCrossRef

17.

Rokkas T, Pistiolas D, Sechopoulos P, Robotis I, Margantinis G (2007) The long-term impact of Helicobacter pylori eradication on gastric histology: a systematic review and meta-analysis. Helicobacter 12(Suppl 2):32–38. doi:10.1111/j.1523-5378.2007.00563.x PubMedCrossRef

18.

Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M et al (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345:784–789. doi:10.1056/NEJMoa001999 PubMedCrossRef

19.

Pimentel-Nunes P, Soares JB, Roncon-Albuquerque R Jr, Dinis-Ribeiro M, Leite-Moreira AF (2010) Toll-like receptors as therapeutic targets in gastrointestinal diseases. Expert Opin Ther Targets 14:347–368. doi:10.1517/14728221003642027 PubMedCrossRef

20.

Rad R, Ballhorn W, Voland P, Eisenacher K, Mages J, Rad L et al (2009) Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology 136:2247–2257. doi:10.1053/j.gastro.2009.02.066 PubMedCrossRef

21.

Rad R, Brenner L, Krug A, Voland P, Mages J, Lang R et al (2007) Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori. Gastroenterology 133:150–163.e3. doi:10.1053/j.gastro.2007.04.071 PubMedCrossRef

22.

Basak C, Pathak SK, Bhattacharyya A, Pathak S, Basu J, Kundu M (2005) 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. J Immunol 174:5672–5680PubMed

23.

Ishihara S, Rumi MA, Kadowaki Y, Ortega-Cava CF, Yuki T, Yoshino N et al (2004) Essential role of MD-2 in TLR4-dependent signaling during Helicobacter pylori-associated gastritis. J Immunol 173:1406–1416PubMed

24.

Kawahara T, Kuwano Y, Teshima-Kondo S, Kawai T, Nikawa T, Kishi K et al (2001) Toll-like receptor 4 regulates gastric pit cell responses to Helicobacter pylori infection. J Med Investig 48:190–197

25.

Smith MF Jr, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K et al (2003) 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. J Biol Chem 278:32552–32560. doi:10.1074/jbc.M305536200 PubMedCrossRef

26.

Torok AM, Bouton AH, Goldberg JB (2005) Helicobacter pylori induces interleukin-8 secretion by Toll-like receptor 2- and Toll-like receptor 5-dependent and -independent pathways. Infect Immun 73:1523–1531. doi:10.1128/IAI.73.3.1523-1531.2005 PubMedCrossRef

27.

Lee SK, Stack A, Katzowitsch E, Aizawa SI, Suerbaum S, Josenhans C (2003) Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5. Microbes Infect 5:1345–1356PubMedCrossRef

28.

Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM et al (2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci USA 102:9247–9252. doi:10.1073/pnas.0502040102 PubMedCrossRef

29.

Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM Jr (2004) Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis 189:1914–1920. doi:10.1086/386289 PubMedCrossRef

30.

Schmausser B, Andrulis M, Endrich S, Lee SK, Josenhans C, Muller-Hermelink HK et al (2004) Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol 136:521–526. doi:10.1111/j.1365-2249.2004.02464.x PubMedCrossRef

31.

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 295:179–185PubMedCrossRef

32.

Hopkins PA, Sriskandan S (2005) Mammalian Toll-like receptors: to immunity and beyond. Clin Exp Immunol 140:395–407. doi:10.1111/j.1365-2249.2005.02801.x PubMedCrossRef

33.

Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446–458. doi:10.1038/nri1630 PubMedCrossRef

34.

Ortega-Cava CF, Ishihara S, Rumi MA, Kawashima K, Ishimura N, Kazumori H et al (2003) Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J Immunol 170:3977–3985PubMed

35.

French SW, Oliva J, French BA, Li J, Bardag-Gorce F Alcohol, nutrition and liver cancer: role of Toll-like receptor signaling. World J Gastroenterol 16:1344–1348

36.

Fukata M, Abreu MT (2008) Role of Toll-like receptors in gastrointestinal malignancies. Oncogene 27:234–243. doi:10.1038/sj.onc.1210908 PubMedCrossRef

37.

Achyut BR, Ghoshal UC, Moorchung N, Mittal B (2007) Association of Toll-like receptor-4 (Asp299Gly and Thr399Ileu) gene polymorphisms with gastritis and precancerous lesions. Hum Immunol 68:901–907. doi:10.1016/j.humimm.2007.10.006 PubMedCrossRef

38.

Hishida A, Matsuo K, Goto Y, Mitsuda Y, Hiraki A, Naito M et al (2009) Toll-like receptor 4 +3725 G/C polymorphism, Helicobacter pylori seropositivity, and the risk of gastric atrophy and gastric cancer in Japanese. Helicobacter 14:47–53. doi:10.1111/j.1523-5378.2009.00659.x PubMedCrossRef

39.

Tahara T, Arisawa T, Wang F, Shibata T, Nakamura M, Sakata M et al (2007) Toll-like receptor 2–196 to 174del polymorphism influences the susceptibility of Japanese people to gastric cancer. Cancer Sci 98:1790–1794. doi:10.1111/j.1349-7006.2007.00590.x PubMedCrossRef

40.

Tahara T, Arisawa T, Wang F, Shibata T, Nakamura M, Sakata M et al (2008) Toll-like receptor 2 (TLR) -196 to 174del polymorphism in gastro-duodenal diseases in Japanese population. Dig Dis Sci 53:919–924. doi:10.1007/s10620-007-9950-x PubMedCrossRef

41.

la Trejo-de OA, Torres J, Perez-Rodriguez M, Camorlinga-Ponce M, Luna LF, Abdo-Francis JM et al (2008) TLR4 single-nucleotide polymorphisms alter mucosal cytokine and chemokine patterns in Mexican patients with Helicobacter pylori-associated gastroduodenal diseases. Clin Immunol 129:333–340. doi:10.1016/j.clim.2008.07.009 CrossRef

42.

Chang YJ, Wu MS, Lin JT, Chen CC (2005) Helicobacter pylori-Induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation. J Immunol 175:8242–8252PubMed

43.

Chang YJ, Wu MS, Lin JT, Sheu BS, Muta T, Inoue H et al (2004) Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. Mol Pharmacol 66:1465–1477. doi:10.1124/mol.104.005199 PubMedCrossRef

44.

Chochi K, Ichikura T, Kinoshita M, Majima T, Shinomiya N, Tsujimoto H et al (2008) Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin Cancer Res 14:2909–2917. doi:10.1158/1078-0432.CCR-07-4467 PubMedCrossRef

Title: Increased Expression of Toll-like Receptors (TLR) 2, 4 and 5 in Gastric Dysplasia
Authors: Pedro Pimentel-Nunes
Luís Afonso
Paula Lopes
Roberto Roncon-Albuquerque Jr
Nádia Gonçalves
Rui Henrique
Luís Moreira-Dias
Adelino F. Leite-Moreira
Mário Dinis-Ribeiro
Publication date: 01-09-2011
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 3/2011
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-011-9368-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2011

Giant Bilateral Symptomatic Adrenal Myelolipomas Associated with Congenital Adrenal Hyperplasia

Cellular and Molecular Mechanisms in the Two Major Forms of Inflammatory Bowel Disease

Epstein-Barr Virus and Breast Cancer: Lack of Evidence for an Association in Iranian Women

Distribution, Incidence, and Prognosis in Neuroendocrine Tumors: a Population Based Study from a Cancer Registry

Expressions of Topoisomerase IIα and BCRP in Metastatic Cells are Associated with Overall Survival in Small Cell Lung Cancer Patients

Glucocorticoid Receptor Expression and Antiproliferative Effect of Dexamethasone on Human Melanoma Cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer