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.

  • Introduction
  • Published:

Toll-like receptors in cancer

Oncogene volume 27, pages 158–160 (2008)Cite this article

This special issue comprises 10 reviews that discuss the potential of targeting a family of receptors termed the Toll-like receptors (TLRs) in cancer. With one drug already in the clinic for basal cell carcinoma (the TLR7 agonist imiquimod) and several clinical trials underway for other TLR-targeted drugs for various other malignancies, the clinical interest in TLRs continues to grow. Also of importance are fundamental studies on the role of TLRs in different types of cancer, notably in leukaemias, prostate cancer, ovarian cancer and gastrointestinal malignancies. These studies are revealing new mechanisms underlying tumorigenesis and also the capacity of the immune system to limit tumour development and growth. Agents that activate TLRs, either alone or possibly more importantly in combination with other approaches, including radiation therapy and chemotherapy, could have great potential as novel anticancer agents. Equally however, inhibiting certain TLRs in inflammation-associated cancers might yield new therapies.

Immunologists were first alerted to the importance of TLRs in 1997, with a description of human Toll (subsequently named TLR4), a protein expressed on macrophages that when active was pro-inflammatory (Medzhitov and Janeway, 1997). Toll had in fact first been described in Drosophila as a protein important in development (Anderson et al., 1985). It was subsequently shown that Toll also plays a key role in antifungal defence in Drosophila (Lemaitre et al., 1996), opening the way for studies on TLRs in the innate immune system of other organisms. This led to an intensive and highly productive period of research, which revealed a great deal of complexity in the innate immune system and provided a key ‘missing link’ in the events that occur during host defence that lead to both innate and adaptive immunity. TLRs also provided the mechanism, whereby inflammatory cytokines are induced during infection and also in tissue injury, since they sense microbial products or products of inflamed tissues, and trigger signalling pathways culminating in the activation of the key transcription factor NF-κB (Doyle and O’Neill, 2006). There are 10 TLRs in humans that recognize various microbial products, and they signal via a specific set of adapter proteins termed MyD88, Mal, Trif and Tram (O’Neill and Bowie, 2007). For obvious reasons, they have been mostly studied in the context of immunity to microbes and also during inflammation, and have been implicated in such clinical conditions as septic shock, inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosis (O’Neill, 2006). However, researchers interested in cancer, and most particularly, cancer associated with inflammation, have also developed a strong interest in TLRs. This interest can in fact be dated back over 100 years, when William Coley demonstrated that crude microbial extracts (most probably, streptococci) when given repeatedly, could promote an antitumour response in several different types of cancer. It is highly likely that these extracts were in part acting via TLRs to promote an immune response to tumours. Another important finding prior to the discovery of TLRs was the observation that the BCG vaccine has efficacy in bladder cancer, and recently, it has been shown that this effect is likely to be due to the activation of TLR2 and -4 (Uehori et al., 2003). As is often the case in medical research therefore, others had already made clinical observations that are now explicable in molecular terms because of the advances made in molecular and cellular biology.

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

References

  • Anderson KV, Jurgens G, Nusslein-Volhard C . (1985). Establishment of dorsal–ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 42: 779–789.

    Article  CAS  Google Scholar 

  • Doyle SL, O’Neill LAJ . (2006). Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72: 1102–1113.

    Article  CAS  Google Scholar 

  • Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ et al. (2006). Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci USA 103: 7753–7758.

    Article  CAS  Google Scholar 

  • Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA . (1996). The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86: 973–983.

    Article  CAS  Google Scholar 

  • Medzhitov R, Janeway Jr CA . (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394–397.

    Article  CAS  Google Scholar 

  • O’Neill LA . (2006). Targeting signal transduction as a strategy to treat inflammatory diseases. Nat Rev Drug Discov 5: 549–563.

    Article  Google Scholar 

  • O’Neill LA, Bowie AG . (2007). The family of five: TIR domain containing adapters in TLR signalling. Nat Rev Immunol 7: 353–364.

    Article  Google Scholar 

  • Uehori J, Matsumoto M, Tsuji S, Akazawa T, Takeuchi O, Akira S et al. (2003). Simultaneous blocking of human Toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette-Guerin peptidoglycan. Infect Immun 71: 4238–4249.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity College, Dublin, Ireland

    L A J O'Neill

Authors
  1. L A J O'Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L A J O'Neill.

Rights and permissions

Reprints and permissions

About this article

Cite this article

O'Neill, L. Toll-like receptors in cancer. Oncogene 27, 158–160 (2008). https://doi.org/10.1038/sj.onc.1210903

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210903

This article is cited by

Search

Advanced search

Quick links