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Tumorigenesis

Innate response

Nature Reviews Cancer volume 7, page 569 (2007)Cite this article

Michael Karin and colleagues were interested in finding a molecular explanation for the sex-based disparity in the incidence of hepatocellular carcinoma (HCC), a disease that affects 3–5 times more men than women. Previous studies have shown that oestrogen is protective against HCC in mice, so Karin and colleagues investigated further. Using mice treated with the chemical carcinogen diethylnitrosamine (DEN), which induces hepatocyte cell death, an inflammatory response and tissue repair, they found that DEN induced higher circulating levels of interleukin 6 (IL6) in males than females. Further analyses showed that Kupffer cells (specialized liver macrophages) produced this IL6, and that this required MYD88, a protein adaptor for toll-like receptors (TLRs) that are part of the innate immune response. MYD88 is also activated in response to some inflammatory cytokines, and has been implicated in tissue repair processes. Myd88-null male mice had a reduced incidence of HCC in response to treatment with DEN.

It seems likely that MYD88 is activated as part of the Kupffer cell response to necrotic hepatocytes produced by DEN, resulting in the induction of IL6. Oestrogen is probably protective because it limits IL6 transcription by reducing the activity of the transcription factors nuclear factor κB and C/EPBβ. These authors suggest that men at risk of developing HCC might benefit from treatment with oestrogen analogues that can inhibit NFκB activation without inducing feminization.

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ORIGINAL RESEARCH PAPERS

  1. Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in Myd88-dependent IL6 production. Science 317, 121–124 (2007)

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  2. Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein Myd88. Science 317, 124–127 (2007)

    Article  CAS  Google Scholar 

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Authors
  1. Nicola McCarthy
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McCarthy, N. Innate response. Nat Rev Cancer 7, 569 (2007). https://doi.org/10.1038/nrc2206

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  • DOI: https://doi.org/10.1038/nrc2206

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