1. Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
2. The Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
3. Goldyne Savad Institute of Gene Therapy, Jerusalem 91120, Israel
4. Hematology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem 91120, Israel
5. These authors contributed equally to this work

Correspondence to: Eli Pikarsky^1,5Yinon Ben-Neriah² Email: peli@hadassah.org.il
Email: yinon@cc.huji.ac.il

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 B (NF-B), a hallmark of inflammatory responses³ that is frequently detected in tumours^{4, 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-B through upregulation of tumour-necrosis factor- (TNF) in adjacent endothelial and inflammatory cells. Switching off NF-B in mice from birth to seven months of age, using a hepatocyte-specific inducible IB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-B inhibition through anti-TNF treatment or induction of IB-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-B is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.

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