Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Cancers take their Toll—the function and regulation of Toll-like receptors in cancer cells

Oncogene volume 27, pages 225–233 (2008)Cite this article

Abstract

Cancer could be deemed as an abnormal and uncontrolled tissue repair process. Therefore, it would not be surprising that factors that function in the tissue repair process, such as cytokines, chemokines, growth factors and Toll-like receptor (TLR) ligands, as well as growth signals for compensatory proliferation, would also be key factors in regulating and enhancing cancer progression. The TLR pathways, which play a critical role in tissue repair, are also key regulators in cancer progression as well as chemoresistance. TLRs serve as cell surface sensors that can initiate pathways leading to proliferation and chemoresistance; as well as mediators that are able to regulate the infiltrating immune cells to provide further support for cancer progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Akira S, Yamamoto M, Takeda K . (2003). Role of adapters in Toll-like receptor signalling. Biochem Soc Trans 31: 637–642.

    Article  CAS  Google Scholar 

  • Alvero AB, O'Malley D, Brown D, Kelly G, Garg M, Chen W et al. (2006). Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells. Cancer 106: 599–608.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Barton GM, Medzhitov R . (2004). Toll signaling: RIPping off the TNF pathway. Nat Immunol 5: 472–474.

    Article  CAS  Google Scholar 

  • Beachy PA, Karhadkar SS, Berman DM . (2004). Mending and malignancy. Nature 431: 402.

    Article  CAS  Google Scholar 

  • Ben-Hur H, Gurevich P, Ben-Arie A, Huszar M, Berman V, Tendler Y et al. (2000a). Apoptosis and apoptosis-related proteins (Fas, Fas ligand, bcl-2, p53) in macrophages of human ovarian epithelial tumors. Eur J Gynaecol Oncol 21: 141–145.

    CAS  PubMed  Google Scholar 

  • Ben-Hur H, Gurevich P, Huszar M, Ben-Arie A, Berman V, Tendler Y et al. (2000b). Apoptosis and apoptosis-related proteins (Fas, Fas ligand, Blc-2, p53) in lymphoid elements of human ovarian tumors. Eur J Gynaecol Oncol 21: 53–57.

    CAS  PubMed  Google Scholar 

  • Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer JL et al. (1998). MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 273: 12203–12209.

    Article  CAS  Google Scholar 

  • Calin GA, Croce CM . (2006). MicroRNA signatures in human cancers. Nat Rev Cancer 6: 857–866.

    Article  CAS  Google Scholar 

  • Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL . (2007a). Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 13: 851–856.

    Article  CAS  Google Scholar 

  • Chen R, Alvero AB, Silasi D-A, Kelly M, Fest S, Leiser A et al. (2007b). Molecular typing of epithelial ovarian cancer: implications on chemoresponse and tumor progression. J Clin Invest (Submitted).

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Covert MW, Leung TH, Gaston JE, Baltimore D . (2005). Achieving stability of lipopolysaccharide-induced NF-kappaB activation. Science 309: 1854–1857.

    Article  CAS  Google Scholar 

  • Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF et al. (2005). Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 102: 3627–3632.

    Article  CAS  Google Scholar 

  • Ernst PB, Takaishi H, Crowe SE . (2001). Helicobacter pylori infection as a model for gastrointestinal immunity and chronic inflammatory diseases. Dig Dis 19: 104–111.

    Article  CAS  Google Scholar 

  • Esquela-Kerscher A, Slack FJ . (2006). Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6: 259–269.

    Article  CAS  Google Scholar 

  • Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K et al. (2005). Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 288: G1055–G1065.

    Article  CAS  Google Scholar 

  • Gannot G, Gannot I, Vered H, Buchner A, Keisari Y . (2002). Increase in immune cell infiltration with progression of oral epithelium from hyperkeratosis to dysplasia and carcinoma. Br J Cancer 86: 1444–1448.

    Article  CAS  Google Scholar 

  • Girling JE, Hedger MP . (2007). Toll-like receptors in the gonads and reproductive tract: emerging roles in reproductive physiology and pathology. Immunol Cell Biol 85: 481–489.

    Article  CAS  Google Scholar 

  • Giudice LC, Kao LC . (2004). Endometriosis. Lancet 364: 1789–1799.

    Article  Google Scholar 

  • Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X et al. (2005). Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 174: 1259–1268.

    Article  CAS  Google Scholar 

  • Gupta RA, Dubois RN . (2001). Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1: 11–21.

    Article  CAS  Google Scholar 

  • Harmey JH, Bucana CD, Lu W, Byrne AM, McDonnell S, Lynch C et al. (2002). Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer 101: 415–422.

    Article  CAS  Google Scholar 

  • He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S et al. (2005). The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 102: 19075–19080.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S et al. (2004). Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303: 1526–1529.

    Article  CAS  Google Scholar 

  • Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH et al. (2005). Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65: 5009–5014.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y et al. (2005). Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11: 1173–1179.

    Article  CAS  Google Scholar 

  • Kamsteeg M, Rutherford T, Sapi E, Hanczaruk B, Shahabi S, Flick M et al. (2003). Phenoxodiol—an isoflavone analog-induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22: 2611–2620.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Koff JL, Shao MX, Kim S, Ueki IF, Nadel JA . (2006). Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade. J Immunol 177: 8693–8700.

    Article  CAS  Google Scholar 

  • Kreuz S, Siegmund D, Rumpf JJ, Samel D, Leverkus M, Janssen O et al. (2004). NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. J Cell Biol 166: 369–380.

    Article  CAS  Google Scholar 

  • Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A . (2002). Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416: 603–607.

    Article  CAS  Google Scholar 

  • Lewis CE, Pollard JW . (2006). Distinct role of macrophages in different tumor microenvironments. Cancer Res 66: 605–612.

    Article  CAS  Google Scholar 

  • Li Q, Withoff S, Verma IM . (2005). Inflammation-associated cancer: NF-kappaB is the lynchpin. Trends Immunol 26: 318–325.

    Article  Google Scholar 

  • Lin WW, Karin M . (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117: 1175–1183.

    Article  CAS  Google Scholar 

  • Lotze MT, Tracey KJ . (2005). High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5: 331–342.

    Article  CAS  Google Scholar 

  • McDermott EP, O'Neill LA . (2002). Ras participates in the activation of p38 MAPK by interleukin-1 by associating with IRAK, IRAK2, TRAF6, and TAK-1. J Biol Chem 277: 7808–7815.

    Article  CAS  Google Scholar 

  • Menard S, Tomasic G, Casalini P, Balsari A, Pilotti S, Cascinelli N et al. (1997). Lymphoid infiltration as a prognostic variable for early-onset breast carcinomas. Clin Cancer Res 3: 817–819.

    CAS  PubMed  Google Scholar 

  • Mor G, Straszewski S, Kamsteeg M . (2002). Role of the Fas/Fas ligand system in female reproductive organs: survival and apoptosis. Biochem Pharmacol 64: 1305–1315.

    Article  CAS  Google Scholar 

  • Mor G, Yue W, Santen RJ, Gutierrez L, Eliza M, Berstein LM et al. (1998). Macrophages, estrogen and the microenvironment of breast cancer. J Steroid Biochem Mol Biol 67: 403–411.

    Article  CAS  Google Scholar 

  • Muzio M, Ni J, Feng P, Dixit VM . (1997). IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278: 1612–1615.

    Article  CAS  Google Scholar 

  • Nakanishi C, Toi M . (2005). Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 5: 297–309.

    Article  CAS  Google Scholar 

  • O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D . (2007). MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA 104: 1604–1609.

    Article  CAS  Google Scholar 

  • Philip M, Rowley DA, Schreiber H . (2004). Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 14: 433–439.

    Article  CAS  Google Scholar 

  • Pidgeon GP, Harmey JH, Kay E, Da Costa M, Redmond HP, Bouchier-Hayes DJ . (1999). The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br J Cancer 81: 1311–1317.

    Article  CAS  Google Scholar 

  • Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S et al. (2004). NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431: 461–466.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW . (2004). Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 23: 2934–2949.

    Article  CAS  Google Scholar 

  • Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS . (2005). Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci USA 102: 99–104.

    Article  CAS  Google Scholar 

  • Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R . (2004). Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118: 229–241.

    Article  CAS  Google Scholar 

  • Rana TM . (2007). Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8: 23–36.

    Article  CAS  Google Scholar 

  • Riman T, Nilsson S, Persson IR . (2004). Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies. Acta Obstet Gynecol Scand 83: 783–795.

    Article  Google Scholar 

  • 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: 588–593.

    Article  CAS  Google Scholar 

  • Ruvkun G . (2001). Molecular biology. Glimpses of a tiny RNA world. Science 294: 797–799.

    Article  CAS  Google Scholar 

  • Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K et al. (2003). Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171: 4304–4310.

    Article  CAS  Google Scholar 

  • Schwartz PE . (2002). Current diagnosis and treatment modalities for ovarian cancer. Cancer Treat Res 107: 99–118.

    PubMed  Google Scholar 

  • Sekizawa A, Amemiya S, Otsuka J, Saito H, Farina A, Okai T et al. (2004). Malignant transformation of endometriosis: application of laser microdissection for analysis of genetic alterations according to pathological changes. Med Electron Microsc 37: 97–100.

    Article  Google Scholar 

  • Shishodia S, Aggarwal BB . (2002). Nuclear factor-kappaB activation: a question of life or death. J Biochem Mol Biol 35: 28–40.

    CAS  PubMed  Google Scholar 

  • Silasi D-A, Alvero AB, Illuzzi J, Kelly MG, Chen R, Fu H-H et al. (2006). MyD88 predicts chemoresistance to paclitaxel in epithelial ovarian cancer. Yale J Biol Med 79: 153–163.

    CAS  PubMed  Google Scholar 

  • Taganov KD, Boldin MP, Chang KJ, Baltimore D . (2006). NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103: 12481–12486.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Tam W, Ben-Yehuda D, Hayward WS . (1997). bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is likely to function through its noncoding RNA. Mol Cell Biol 17: 1490–1502.

    Article  CAS  Google Scholar 

  • Tsan MF . (2006). Toll-like receptors, inflammation and cancer. Semin Cancer Biol 16: 32–37.

    Article  CAS  Google Scholar 

  • Virchow R . (1858). Reizung und Reizbarkeit. Arch Pathol Anat Klin Med 14: 1–63.

    Article  Google Scholar 

  • Virchow R . (1863). Die Krankhaften Geschwulste. Verlag von August Hirschwald: Berlin, pp 57–101.

    Google Scholar 

  • Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F et al. (2006). A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103: 2257–2261.

    Article  CAS  Google Scholar 

  • Werner SL, Barken D, Hoffmann A . (2005). Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 309: 1857–1861.

    Article  CAS  Google Scholar 

  • Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z . (1997). MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7: 837–847.

    Article  CAS  Google Scholar 

  • Wiemer EA . (2007). The role of microRNAs in cancer: no small matter. Eur J Cancer 43: 1529–1544.

    Article  CAS  Google Scholar 

  • Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS et al. (2005). TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308: 1626–1629.

    Article  CAS  Google Scholar 

  • Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA et al. (2004). A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303: 1522–1526.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA

    R Chen

  2. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

    R Chen, A B Alvero, D-A Silasi & G Mor

  3. Department of Oncology, Vejle Hospital, Vejle, Denmark

    K D Steffensen

Authors
  1. R Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A B Alvero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D-A Silasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K D Steffensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Mor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Mor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, R., Alvero, A., Silasi, DA. et al. Cancers take their Toll—the function and regulation of Toll-like receptors in cancer cells. Oncogene 27, 225–233 (2008). https://doi.org/10.1038/sj.onc.1210907

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210907

Keywords

This article is cited by

Search

Advanced search

Quick links