Skip to main content

Advertisement

SpringerLink
Log in

The dual role of TLR3 in metastatic cell line

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Toll-like receptors (TLRs) are members of transmembrane proteins that recognize conserved molecular motifs of viral and bacterial origin and initiate innate immune response. As the role of TLRs in tumors cells is still not clear, our aim was to investigate the role of TLR3 in primary tumor and metastatic cells (SW480, SW620, FaDu and Detroit 562). We have reported here on the dual role of TLR3 in pharynx metastatic cell line (Detroit 562); on one hand TLR3 activation drove cells to apoptosis while on the other its stimulation contributed to tumor progression by altering the expression of tumor promoting genes (PLAUR, RORB) and enhancing the cell migration potential. In addition, we have shown TLR3 signaling pathway is functional in another metastatic cancer cell line (SW620) suggesting TLR3 might be important in the process of tumor metastasis. Since TLR3 agonists have been used in tumor therapy with the aim to activate immune system, scientific contribution of this work is drawing attention to the importance of further work on this topic, especially pro-tumor effect of TLR3, in order to avoid possible side-effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Goto Y, Arigami T, Kitago M et al (2008) Activation of toll-like receptors 2, 3, and 4 on human melanoma cells induces inflammatory factors. Mol Cancer Ther 7:3642–3653

    Article  PubMed  CAS  Google Scholar 

  2. He W, Liu Q, Wang L et al (2007) TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol 44:2850–2859

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Kim WY, Lee JW, Choi JJ et al (2008) Increased expression of toll-like receptor 5 during progression of cervical neoplasia. Int J Gynecol Cancer 18:300–305

    Article  PubMed  CAS  Google Scholar 

  5. Zhou M, McFarland-Mancini MM, Funk HM et al (2009) Toll-like receptor expression in normal ovary and ovarian tumors. Cancer Immunol Immunother 58:1375–1385

    Article  PubMed  CAS  Google Scholar 

  6. Pries R, Hogrefe L, Xie L et al (2008) Induction of c-Myc-dependent cell proliferation through toll-like receptor 3 in head and neck cancer. Int J Mol Med 21:209–215

    PubMed  CAS  Google Scholar 

  7. Xie W, Wang Y, Huang Y et al (2009) Toll-like receptor 2 mediates invasion via activating NF-kappaB in MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun 379:1027–1032

    Article  PubMed  CAS  Google Scholar 

  8. Kelly MG, Alvero AB, Chen R et al (2006) TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 66:3859–3868

    Article  PubMed  CAS  Google Scholar 

  9. Huang B, Zhao J, Shen S et al (2007) Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Res 67:4346–4352

    Article  PubMed  CAS  Google Scholar 

  10. Jasani B, Navabi H, Adams M (2009) Ampligen: a potential toll-like 3 receptor adjuvant for immunotherapy of cancer. Vaccine 27:3401–3404

    Article  PubMed  CAS  Google Scholar 

  11. Salaun B, Coste I, Rissoan MC et al (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176:4894–4901

    PubMed  CAS  Google Scholar 

  12. Salaun B, Lebecque S, Matikainen S et al (2007) Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res 13:4565–4574

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Kishimoto Y, Tani M, Uto-Kondo H et al (2010) Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages. Eur J Nutr 49:119–126

    Article  PubMed  CAS  Google Scholar 

  16. Nagaraj NS, Zacharias W (2007) Cigarette smoke condensate increases cathepsin-mediated invasiveness of oral carcinoma cells. Toxicol Lett 170:134–145

    Article  PubMed  CAS  Google Scholar 

  17. Katono T, Kawato T, Tanabe N et al (2006) Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells. Acta Biochim Biophys Sin 38:874–882

    Article  PubMed  CAS  Google Scholar 

  18. Peng S, Geng J, Sun R et al (2009) Polyinosinic-polycytidylic acid liposome induces human hepatoma cells apoptosis which correlates to the up-regulation of RIG-I like receptors. Cancer Sci 100:529–536

    Article  PubMed  CAS  Google Scholar 

  19. Jura J, Wegrzyn P, Korostynski M et al (2008) Identification of interleukin-1 and interleukin-6-responsive genes in human monocyte-derived macrophages using microarrays. Biochim Biophys Acta 1779:383–389

    PubMed  CAS  Google Scholar 

  20. Harper J, Yan L, Loureiro RM et al (2007) Repression of vascular endothelial growth factor expression by the zinc finger transcription factor ZNF24. Cancer Res 67:8736–8741

    Article  PubMed  CAS  Google Scholar 

  21. Gonzalez-Reyes S, Fernandez JM, Gonzalez LO et al (2011) Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence. Cancer Immunol Immunother 60:217–226

    Article  PubMed  CAS  Google Scholar 

  22. Gonzalez-Reyes S, Marin L, Gonzalez L et al (2010) Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer 10:665

    Article  PubMed  CAS  Google Scholar 

  23. Zigrino P, Kuhn I, Bauerle T et al (2009) Stromal expression of MMP-13 is required for melanoma invasion and metastasis. J Invest Dermatol 129:2686–2693

    Article  PubMed  CAS  Google Scholar 

  24. Iwatsuki M, Mimori K, Yokobori T et al (2010) Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101:293–299

    Article  PubMed  CAS  Google Scholar 

  25. Tang CH, Wei Y (2008) The urokinase receptor and integrins in cancer progression. Cell Mol Life Sci 65:1916–1932

    Article  PubMed  CAS  Google Scholar 

  26. Andreasen PA, Egelund R, Petersen HH (2000) The plasminogen activation system in tumor growth invasion and metastasis. Cell Mol Life Sci 57:25–40

    Article  PubMed  CAS  Google Scholar 

  27. Sheng S (2001) The urokinase-type plasminogen activator system in prostate cancer metastasis. Cancer Metastasis Rev 20:287–296

    Article  PubMed  CAS  Google Scholar 

  28. Lechner M, Lirk P, Rieder J (2005) Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol 15:277–289

    Article  PubMed  CAS  Google Scholar 

  29. Burney S, Caulfield JL, Niles JC et al (1999) The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res 424:37–49

    Article  PubMed  CAS  Google Scholar 

  30. Chin K, Kurashima Y, Ogura T et al (1997) Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells. Oncogene 15:437–442

    Article  PubMed  CAS  Google Scholar 

  31. Tronc F, Mallat Z, Lehoux S et al (2000) Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO. Arterioscler Thromb Vasc Biol 20:E120–E126

    Article  PubMed  CAS  Google Scholar 

  32. Spiecker M, Darius H, Kaboth K et al (1998) Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants. J Leukoc Biol 63:732–739

    PubMed  CAS  Google Scholar 

  33. Gansauge S, Nussler AK, Beger HG et al (1998) Nitric oxide-induced apoptosis in human pancreatic carcinoma cell lines is associated with a G1-arrest and an increase of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. Cell Growth Differ 9:611–617

    PubMed  CAS  Google Scholar 

  34. Kwak JY, Han MK, Choi KS et al (2000) Cytokines secreted by lymphokine-activated killer cells induce endogenous nitric oxide synthesis and apoptosis in DLD-1 colon cancer cells. Cell Immunol 203:84–94

    Article  PubMed  CAS  Google Scholar 

  35. Apte RN, Dotan S, Elkabets M et al (2006) The involvement of IL-1 in tumorigenesis tumor invasiveness metastasis and tumor–host interactions. Cancer Metastasis Rev 25:387–408

    Article  PubMed  CAS  Google Scholar 

  36. Voronov E, Shouval DS, Krelin Y et al (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 100:2645–2650

    Article  PubMed  CAS  Google Scholar 

  37. Paravicini G, Steinmayr M, Andre E et al (1996) The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem Biophys Res Commun 227:82–87

    Article  PubMed  CAS  Google Scholar 

  38. Ulisse S, Baldini E, Sorrenti S et al (2009) The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr Cancer Drug Targets 9:32–71

    Article  PubMed  CAS  Google Scholar 

  39. Rabbani SA, Ateeq B, Arakelian A et al (2010) An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion migration growth and experimental skeletal metastasis in vitro and in vivo. Neoplasia 12:778–788

    PubMed  CAS  Google Scholar 

  40. Liang X, Yang X, Tang Y et al (2008) RNAi-mediated downregulation of urokinase plasminogen activator receptor inhibits proliferation adhesion migration and invasion in oral cancer cells. Oral Oncol 44:1172–1180

    Article  PubMed  CAS  Google Scholar 

  41. Yoneda K, Sugimoto K, Shiraki K et al (2008) Dual topology of functional Toll-like receptor 3 expression in human hepatocellular carcinoma: differential signaling mechanisms of TLR3-induced NF-kappaB activation and apoptosis. Int J Oncol 33:929–936

    PubMed  CAS  Google Scholar 

  42. Khvalevsky E, Rivkin L, Rachmilewitz J et al (2007) TLR3 signaling in a hepatoma cell line is skewed towards apoptosis. J Cell Biochem 100:1301–1312

    Article  PubMed  CAS  Google Scholar 

  43. McCall KD, Harii N, Lewis CJ et al (2007) 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

    Article  PubMed  CAS  Google Scholar 

  44. Schwartz AL, Malgor R, Dickerson E et al (2009) Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res 15:4114–4122

    Article  PubMed  CAS  Google Scholar 

  45. Edelblum KL, Goettel JA, Koyama T et al (2008) TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-kappaB. J Biol Chem 283:29485–29494

    Article  PubMed  CAS  Google Scholar 

  46. Manna SK, Zhang HJ, Yan T et al (1998) Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1. J Biol Chem 273:13245–13254

    Article  PubMed  CAS  Google Scholar 

  47. Manna SK, Kuo MT, Aggarwal BB (1999) Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1. Oncogene 18:4371–4382

    Article  PubMed  CAS  Google Scholar 

  48. Paone A, Galli R, Gabellini C et al (2010) Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha. Neoplasia 12:539–549

    PubMed  CAS  Google Scholar 

  49. Gorlach A, Kietzmann T (2007) Superoxide and derived reactive oxygen species in the regulation of hypoxia-inducible factors. Methods Enzymol 435:421–446

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by the grant number 098-0982464-2394 from The Ministry of Science, Education and Sports, Republic of Croatia.

Author information

Authors and Affiliations

  1. Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10000, Zagreb, Croatia

    Tanja Matijevic & Jasminka Pavelic

Authors
  1. Tanja Matijevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jasminka Pavelic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jasminka Pavelic.

Appendix

Appendix

See Table 5.

Table 5 Genes analyzed in gene array experiments
Full size table

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matijevic, T., Pavelic, J. The dual role of TLR3 in metastatic cell line. Clin Exp Metastasis 28, 701–712 (2011). https://doi.org/10.1007/s10585-011-9402-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-011-9402-z

Keywords

Search

Navigation