Abstract
The causes of sporadic human cancer are seldom recognized, but it is estimated that carcinogen exposure and chronic inflammation are two important underlying conditions for tumour development, the latter accounting for approximately 20% of human cancer1. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated2, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved1. We proposed that activation of the nuclear factor κB (NF-κB), a hallmark of inflammatory responses3 that is frequently detected in tumours4,5, may constitute a missing link between inflammation and cancer. To test this hypothesis, we studied the Mdr2-knockout mouse strain, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma6, a prototype of inflammation-associated cancer7. We monitored hepatitis and cancer progression in Mdr2-knockout mice, and here we show that the inflammatory process triggers hepatocyte NF-κB through upregulation of tumour-necrosis factor-α (TNFα) in adjacent endothelial and inflammatory cells. Switching off NF-κB in mice from birth to seven months of age, using a hepatocyte-specific inducible IκB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-κB inhibition through anti-TNFα treatment or induction of IκB-super-repressor in later stages of tumour development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Our studies thus indicate that NF-κB is essential for promoting inflammation-associated cancer, and is therefore a potential _target for cancer prevention in chronic inflammatory diseases.
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Acknowledgements
Mdr2-knockout mice were a gift from R. P. Oude Elferink and the TALAP1 mice were received from H. Bujard. We are grateful to N. Berger, T. Golub and N. Kidess-Bassir for technical assistance, to A. Hatzubai, O. Mandlboim, N. Lieberman, G. Kojekaro, M. Davis and H. Harel for helping with MRI, FACS, mRNA and protein analysis. We thank K. Meir and M. Oren for discussions and a critical reading of the manuscript. This research was supported by grants from the Israel Science Foundation funded by the Israel Academy for Sciences and Humanities (Center of Excellence Program), Prostate Cancer Foundation Israel—Center of Excellence, German-Israeli Foundation for Scientific Research and Development (GIF, in collaboration with H. Bujard), a grant in memory of H. and F. Brody from H. M. Krueger as trustee of a charitable trust and the Israel Cancer Research Foundation (ICRF). I.S. is supported by the Lady Davis Fellowship Trust.
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Pikarsky, E., Porat, R., Stein, I. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004). https://doi.org/10.1038/nature02924
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DOI: https://doi.org/10.1038/nature02924
