Tumorigenesis: Innate response

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MYD88 is a crucial component of tumorigenesis in tissues that are subject to heightened or disrupted tissue repair and/or renewal pathways, further re-enforcing the link between tissue repair and oncogenesis.

Two papers published recently in Science indicate that an adaptor protein involved in the innate immune response is a crucial component of tumorigenesis in tissues subject to heightened or disrupted tissue repair and/or renewal pathways, and again re-enforce the link between tissue repair and cancer development.


Image courtesy of Nicola McCarthy

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 kappa B and C/EPB beta . These authors suggest that men at risk of developing HCC might benefit from treatment with oestrogen analogues that can inhibit NF kappa B activation without inducing feminization.

Seth Rakoff-Nahoum and Ruslan Medzhitov have shown that MYD88 is required for intestinal tumorigenesis in mice. The fact that mutation of adenomatosis polyposis coli (APC), a gene also involved in renewal of the intestinal epithelium, is tumorigenic, prompted them to investigate the effect of MYD88 ablation in intestinal tumour prone Apc^+/Min mice. Loss of MYD88 significantly impaired tumour formation in these mice, and the evidence indicates that MYD88 affects the progression from micro- to macro-adenomas and not tumour initiation. Analyses of gene signatures in size-matched adenomas between Myd88 null and wild-type Apc^+/Min mice indicated that MYD88 controls the expression of many genes implicated in tissue repair, inflammation and tumorigenesis. It is not yet clear in this model how the TLR–MYD88 pathway is activated , or whether MYD88 expression is important in human intestinal carcinogenesis.

Both papers add to the increasing evidence that activation of the TLR pathway is involved in tumorigenesis.

Nicola McCarthy

References

Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in Myd88-dependent IL6 production. Science 317, 121–124 (2007) | Article | PubMed |
Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein Myd88. Science 317, 124–127 (2007) | Article | PubMed |