Immune pathogenesis of hepatocellular carcinoma. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. The transcription factor NF-κB: control of oncogenesis and cancer therapy resistance. Carcinogenesis in mouse and human cells: parallels and paradoxes. 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.Ĭoussens, L. 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. 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. 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. To test this hypothesis, we studied the Mdr2-knockout mouse strain, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma 6, a prototype of inflammation-associated cancer 7. We proposed that activation of the nuclear factor κB (NF-κB), a hallmark of inflammatory responses 3 that is frequently detected in tumours 4, 5, may constitute a missing link between inflammation and cancer. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated 2, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved 1. 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 cancer 1.
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