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Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4, and 9 in prostate cancer.

Methods

The expression levels of TLR3, TLR4, and TLR9 were analyzed on tumors from 133 patients with prostate cancer. The analyses were performed by immunohistochemistry on tissue arrays and real time-PCR.

Results

Cancerous cells showed high expression levels of TLRs compared with controls. Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4, and TLR9. In addition, the tumors that showed high TLR3 or TLR9 expression levels were significantly associated with higher probability of biochemical recurrence.

Conclusion

TLR expression is associated with prostate cancer with recurrence and the role of TLR receptors in the biology of malignancy merits study. Therapeutic strategies to boost or block TLRs may be of interest.

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References

  1. Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ, Haas GP (1994) High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20–69: an autopsy study of 249 cases. In Vivo 8:439–443

    CAS  PubMed  Google Scholar 

  2. Hsing AW, Chokkalingam AP (2006) Prostate cancer epidemiology. Front Biosci 11:1388–1413

    Article  CAS  PubMed  Google Scholar 

  3. Khatami M (2008) ‘Yin and Yang’ in inflammation: duality in innate immune cell function and tumorigenesis. Expert Opin Biol Ther 8:1461–1472

    Article  CAS  PubMed  Google Scholar 

  4. Ferrantini M, Capone I, Belardelli F (2008) Dendritic cells and cytokines in immune rejection of cancer. Cytokine Growth Factor Rev 19:93–107

    Article  CAS  PubMed  Google Scholar 

  5. Khatami M (2005) Developmental phases of inflammation-induced massive lymphoid hyperplasia and extensive changes in epithelium in an experimental model of allergy: implications for a direct link between inflammation and carcinogenesis. Am J Ther 12:117–126

    Article  PubMed  Google Scholar 

  6. Risques RA, Rabinovitch PS, Brentnall TA (2006) Cancer surveillance in inflammatory bowel disease: new molecular approaches. Curr Opin Gastroenterol 22:382–390

    Article  CAS  PubMed  Google Scholar 

  7. Smyth MJ, Trapani JA (2001) Lymphocyte-mediated immunosurveillance of epithelial cancers? Trends Immunol 22:409–411

    Article  CAS  PubMed  Google Scholar 

  8. Burnet M (1957) Cancer; a biological approach. I. The processes of control. Br Med J 1:779–786

    Article  CAS  PubMed  Google Scholar 

  9. Stanley MA, Pett MR, Coleman N (2007) HPV: from infection to cancer. Biochem Soc Trans 35:1456–1460

    Article  CAS  PubMed  Google Scholar 

  10. Costantini S, Capone F, Guerriero E, Castello G (2009) An approach for understanding the inflammation and cancer relationship. Immunol Lett 126:91–92

    Article  CAS  PubMed  Google Scholar 

  11. Hochreiter WW, Nadler RB, Koch AE, Campbell PL, Ludwig M, Weidner W, Schaeffer AJ (2000) Evaluation of the cytokines interleukin 8 and epithelial neutrophil activating peptide 78 as indicators of inflammation in prostatic secretions. Urology 56:1025–1029

    Article  CAS  PubMed  Google Scholar 

  12. Fujita K, Ewing CM, Sokoll LJ, Elliott DJ, Cunningham M, De Marzo AM, Isaacs WB, Pavlovich CP (2008) Cytokine profiling of prostatic fluid from cancerous prostate glands identifies cytokines associated with extent of tumor and inflammation. Prostate 68:872–882

    Article  CAS  PubMed  Google Scholar 

  13. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825

    Article  CAS  PubMed  Google Scholar 

  14. O’Neill LA, Bryant CE, Doyle SL (2009) Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev 61:177–197

    Article  PubMed  Google Scholar 

  15. Lossos IS, Alizadeh AA, Rajapaksa R, Tibshirani R, Levy R (2003) HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma. Blood 101:433–440

    Article  CAS  PubMed  Google Scholar 

  16. Gohji K, Fujimoto N, Hara I, Fujii A, Gotoh A, Okada H, Arakawa S, Kitazawa S, Miyake H, Kamidono S (1998) Serum matrix metalloproteinase-2 and its density in men with prostate cancer as a new predictor of disease extension. Int J Cancer 79:96–101

    Article  CAS  PubMed  Google Scholar 

  17. Maeda H, Okamoto T, Akaike T (1998) Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals. Biol Chem 379:193–200

    Article  CAS  PubMed  Google Scholar 

  18. Chin AI, Miyahira AK, Covarrubias A, Teague J, Guo B, Dempsey PW, Cheng G (2010) Toll-like receptor 3-mediated suppression of TRAMP prostate cancer shows the critical role of type I interferons in tumor immune surveillance. Cancer Res 70:2595–2603

    Article  CAS  PubMed  Google Scholar 

  19. Nicodemus CF, Wang L, Lucas J, Varghese B, Berek JS (2010) Toll-like receptor-3 as a target to enhance bioactivity of cancer immunotherapy. Am J Obstet Gynecol 608:e1–e8

    Google Scholar 

  20. Paone A, Starace D, Galli R, Padula F, De Cesaris P, Filippini A, Ziparo E, Riccioli A (2008) Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis 29:1334–1342

    Article  CAS  PubMed  Google Scholar 

  21. Zheng SL, Augustsson-Balter K, Chang B, Hedelin M, Li L, Adami HO, Bensen J, Li G, Johnasson JE, Turner AR (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

    Article  CAS  PubMed  Google Scholar 

  22. Vaisanen MR, Vaisanen T, Jukkola-Vuorinen A, Vuopala KS (2010) Expression of toll-like receptor-9 is increased in poorly differentiated prostate tumors. Prostate 70:817–824

    Article  PubMed  Google Scholar 

  23. Di JM, Pang J, Pu XY, Zhang Y, Liu XP, Fang YQ, Ruan XX, Gao X (2009) Toll-like receptor 9 agonists promoter IL-8 and TGF-beta 1 production via activation of nuclear factor kappaB in PC-3 cells. Cancer Genet Cytogenet 192:60–67

    Article  CAS  PubMed  Google Scholar 

  24. Ilvesaro JM, Merrell MA, Swain TM, Davidson J (2007) Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate 67:774–781

    Article  CAS  PubMed  Google Scholar 

  25. Flemming ID, Cooper IS, Hemson DE (1997) The 1992 TNM classification. American Joint Committtee on Cancer Staging Manual, 5th edn. JB Lippincott, Philadelphia, pp 219–222

    Google Scholar 

  26. (ISUP), TISoUP (2005) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 29:1228

    Article  Google Scholar 

  27. Parker RL, Huntsman DG, Lesack DW, Cupples JB, Grant DR, Akbari M, Gilks CB (2002) Assessment of interlaboratory variation in the immunohistochemical determination of estrogen receptor status using a breast cancer tissue microarray. Am J Clin Pathol 117:723–728

    Article  PubMed  Google Scholar 

  28. Liu N, Lapcevich RK, Underhill CB, Han Z, Gao F, Swartz G, Plum SM, Zhang L, Green SJ (2001) Metastatin: a hyaluronan-binding complex from cartilage that inhibits tumor growth. Cancer Res 61:1022–1028

    CAS  PubMed  Google Scholar 

  29. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176:4894–4901

    CAS  PubMed  Google Scholar 

  30. Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, Mayer L, Unkeless JC, Xiong H (2005) Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65:5009–5014

    Article  CAS  PubMed  Google Scholar 

  31. Wolska A, Lech-Maranda E, Robak T (2009) Toll-like receptors and their role in carcinogenesis and anti-tumor treatment. Cell Mol Biol Lett 14:248–272

    Article  CAS  PubMed  Google Scholar 

  32. Kundu SD, Lee C, Billips BK, Habermacher GM, Zhang Q, Liu V, Wong LY, Klumpp DJ, Thumbikat P (2008) The toll-like receptor pathway: a novel mechanism of infection-induced carcinogenesis of prostate epithelial cells. Prostate 68:223–229

    Article  CAS  PubMed  Google Scholar 

  33. Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, Visintin I, Rutherford T, Mor G (2006) TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 66:3859–3868

    Article  CAS  PubMed  Google Scholar 

  34. Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S, Hsu D, Xu R, Harpaz N, Dannenberg AJ (2007) Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133:1869–1881

    Article  CAS  PubMed  Google Scholar 

  35. Swann JB, Vesely MD, Silva A, Sharkey J, Akira S, Schreiber RD, Smyth MJ (2008) Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA 105:652–656

    Article  CAS  PubMed  Google Scholar 

  36. Sato Y, Goto Y, Narita N, Hoon DS (2009) Cancer cells expressing toll-like receptors and the tumor microenvironment. Cancer Microenviron 2:205–214

    Article  PubMed  Google Scholar 

  37. Stark JR, Wiklund F, Gronberg H, Schumacher F, Sinnott JA, Stampfer MJ, Mucci LA, Kraft P (2009) Toll-like receptor signaling pathway variants and prostate cancer mortality. Cancer Epidemiol Biomarkers Prev 18:1859–1863

    Article  CAS  PubMed  Google Scholar 

  38. Hoebe K, Janssen E, Beutler B (2004) The interface between innate and adaptive immunity. Nat Immunol 5:971–974

    Article  CAS  PubMed  Google Scholar 

  39. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37

    Article  PubMed  Google Scholar 

  40. Denhardt DT, Feng B, Edwards DR, Cocuzzi ET, Malyankar UM (1993) Tissue inhibitor of metalloproteinases (TIMP, aka EPA): structure, control of expression and biological functions. Pharmacol Ther 59:329–341

    Article  CAS  PubMed  Google Scholar 

  41. Yamauchi H, Stearns V, Hayes DF (2001) When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol 19:2334–2356

    CAS  PubMed  Google Scholar 

  42. Escaff S, Fernandez JM, Gonzalez LO, Suarez A, Gonzalez-Reyes S, Gonzalez JM, Vizoso FJ (2010) Study of matrix metalloproteinases and their inhibitors in prostate cancer. Br J Cancer 102:922–929

    Article  CAS  PubMed  Google Scholar 

  43. Saenz-Lopez P, Carretero R, Cozar JM, Romero JM, Canton J, Vilchez JR, Tallada M, Garrido F, Ruiz-Cabello F (2008) Genetic polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer. BMC Cancer 8:382

    Article  PubMed  Google Scholar 

  44. Lindmark F, Zheng SL, Wiklund F, Balter KA, Sun J, Chang B, Hedelin M, Clark J, Johansson JE, Meyers DA (2005) Interleukin-1 receptor antagonist haplotype associated with prostate cancer risk. Br J Cancer 93:493–497

    Article  CAS  PubMed  Google Scholar 

  45. Ricote M, Garcia-Tunon I, Bethencourt FR, Fraile B, Paniagua R, Royuela M (2004) Interleukin-1 (IL-1alpha and IL-1beta) and its receptors (IL-1RI, IL-1RII, and IL-1Ra) in prostate carcinoma. Cancer 100:1388–1396

    Article  CAS  PubMed  Google Scholar 

  46. Lebel-Binay S, Thiounn N, De Pinieux G, Vieillefond A, Debre B, Bonnefoy JY, Fridman WH, Pages F (2003) IL-18 is produced by prostate cancer cells and secreted in response to interferons. Int J Cancer 106:827–835

    Article  CAS  PubMed  Google Scholar 

  47. Faupel-Badger JM, Kidd LC, Albanes D, Virtamo J, Woodson K, Tangrea JA (2008) Association of IL-10 polymorphisms with prostate cancer risk and grade of disease. Cancer Causes Control 19:119–124

    Article  PubMed  Google Scholar 

  48. Zabaleta J, Su LJ, Lin HY, Sierra RA, Hall MC, Sartor AO, Clark PE, Hu JJ, Ochoa AC (2009) Cytokine genetic polymorphisms and prostate cancer aggressiveness. Carcinogenesis 30:1358–1362

    Article  CAS  PubMed  Google Scholar 

  49. Nishiya T, DeFranco AL (2004) Ligand-regulated chimeric receptor approach reveals distinctive subcellular localization and signaling properties of the Toll-like receptors. J Biol Chem 279(18):19008–19017

    Article  CAS  PubMed  Google Scholar 

  50. Platz J, Beisswenger C, Dalpke A, Koczulla R, Pinkenburg O, Vogelmeier C, Bals R (2004) Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J Immunol 173:1219–1223

    CAS  PubMed  Google Scholar 

  51. 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

    Article  CAS  PubMed  Google Scholar 

  52. Droemann D, Albrecht D, Gerdes J, Ulmer AJ, Branscheid D, Vollmer E, Dalhoff K, Zabel P, Goldmann T (2005) Human lung cancer cells express functionally active Toll-like receptor 9. Respir Res 6:1

    Article  PubMed  Google Scholar 

  53. Merrell MA, Ilvesaro JM, Lehtonen N, Sorsa T, Gehrs B, Rosenthal E, Chen D, Shackley B, Harris KW, Selander KS (2006) Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res 4:437–447

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. Nickel JC, Moon T (2005) Chronic bacterial prostatitis: an evolving clinical enigma. Urology 66:2–8

    Article  PubMed  Google Scholar 

  56. Tanner MA, Shoskes D, Shahed A, Pace NR (1999) Prevalence of corynebacterial 16S rRNA sequences in patients with bacterial and “nonbacterial” prostatitis. J Clin Microbiol 37:1863–1870

    CAS  PubMed  Google Scholar 

  57. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217

    Article  CAS  PubMed  Google Scholar 

  58. Nelson WG, De Marzo AM, Deweese TL, Isaacs WB (2004) The role of inflammation in the pathogenesis of prostate cancer. J Urol 172:S6–S11

    Article  CAS  PubMed  Google Scholar 

  59. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78

    Article  CAS  PubMed  Google Scholar 

  60. Stock D, Groome PA, Siemens DR (2008) Inflammation and prostate cancer: a future target for prevention and therapy? Urol Clin North Am 35:117–130

    Article  PubMed  Google Scholar 

  61. Amling CL, Blute ML, Bergstralh EJ, Seay TM, Slezak J, Zincke H (2000) Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol 164:101–105

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully thank Dr. Esperanza Fernández for helpful discussion and critical and careful reading. This work was supported by IPSEN PHARMA S.A. and FICYT (IB08-170).

Conflict of interest

The authors indicated no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Servicio Urología, Hospital de Jove, Gijón, Spain

    Aurelio Suárez & Safwan Escaff

  2. Unidad de Investigación, Hospital de Jove, Gijón, Spain

    Salomé González-Reyes, Luis O. González, Alina Aguirre, José M. González, Safwan Escaff & Francisco J. Vizoso

  3. Servicio de Urología, Hospital Universitario Central de Asturias, Oviedo, Spain

    Jesús M. Fernández

  4. Servicio de Cirugía General, Hospital de Jove, Avda. Eduardo Castro s/n, 33920, Gijón, Asturias, Spain

    Francisco J. Vizoso

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  1. Salomé González-Reyes
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  2. Jesús M. Fernández
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  3. Luis O. González
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  4. Alina Aguirre
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  5. Aurelio Suárez
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  6. José M. González
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  8. Francisco J. Vizoso
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Corresponding author

Correspondence to Francisco J. Vizoso.

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González-Reyes, S., Fernández, J.M., González, L.O. et al. Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence. Cancer Immunol Immunother 60, 217–226 (2011). https://doi.org/10.1007/s00262-010-0931-0

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  • DOI: https://doi.org/10.1007/s00262-010-0931-0

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