Journal ArticleDOI
NF-κB functions as a tumour promoter in inflammation-associated cancer
Eli Pikarsky,Rinnat M. Porat,Ilan Stein,Rinat Abramovitch,Sharon Amit,Shafika Kasem,Elena Gutkovich-Pyest,Simcha Urieli-Shoval,Eithan Galun,Yinon Ben-Neriah +9 more
TLDR
It is shown that the inflammatory process triggers hepatocyte NF-κB through upregulation of tumour-necrosis factor-α (TNFα) in adjacent endothelial and inflammatory cells, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.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 cancer. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. We proposed that activation of the nuclear factor kappaB (NF-kappaB), a hallmark of inflammatory responses that is frequently detected in tumours, 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 carcinoma, a prototype of inflammation-associated cancer. We monitored hepatitis and cancer progression in Mdr2-knockout mice, and here we show that the inflammatory process triggers hepatocyte NF-kappaB through upregulation of tumour-necrosis factor-alpha (TNFalpha) in adjacent endothelial and inflammatory cells. Switching off NF-kappaB in mice from birth to seven months of age, using a hepatocyte-specific inducible IkappaB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-kappaB inhibition through anti-TNFalpha treatment or induction of IkappaB-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-kappaB is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.read more
Citations
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Cancer-related inflammation.
TL;DR: The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Journal ArticleDOI
Immunity, Inflammation, and Cancer
TL;DR: The principal mechanisms that govern the effects of inflammation and immunity on tumor development are outlined and attractive new targets for cancer therapy and prevention are discussed.
Journal ArticleDOI
Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome
Jérôme Galon,Anne Costes,Fátima Sánchez-Cabo,Amos Kirilovsky,Bernhard Mlecnik,Christine Lagorce-Pagès,Marie Tosolini,Matthieu Camus,Anne Berger,Philippe Wind,Franck Zinzindohoué,Patrick Bruneval,Paul-Henri Cugnenc,Zlatko Trajanoski,Wolf H. Fridman,Franck Pagès +15 more
TL;DR: In situ analysis of tumor-infiltrating immune cells may be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
Journal ArticleDOI
Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis
TL;DR: A detailed understanding of epidemiologic factors and molecular mechanisms associated with HCC ultimately could improve current concepts for screening and treatment of this disease.
Journal ArticleDOI
STATs in cancer inflammation and immunity: a leading role for STAT3
TL;DR: Signal transducer and activator of transcription proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer, and STAT3 is a promising target to redirect inflammation for cancer therapy.
References
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Journal ArticleDOI
Inflammation and cancer
Lisa M. Coussens,Zena Werb +1 more
TL;DR: It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration.
Journal ArticleDOI
NF-kappaB regulation in the immune system.
Qiutang Li,Inder M. Verma +1 more
TL;DR: The role of NF-κB proteins as potential therapeutic targets in clinical applications and their role in the immune system and inflammatory diseases are discussed.
Journal ArticleDOI
IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.
Florian R. Greten,Lars Eckmann,Tim F. Greten,Jin Mo Park,Zhi-Wei Li,Laurence J. Egan,Laurence J. Egan,Martin F. Kagnoff,Michael Karin +8 more
TL;DR: It is shown that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size, which is linked to increased epithelial apoptosis during tumor promotion.
Journal ArticleDOI
Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B.
TL;DR: Results indicate that RelA controls inducible, but not basal, transcription in NF-κB-regulated pathways, and suggest that tumour necrosis factor-mediated induction of messenger RNAs for IκBα and granulocyte/macrophage colony stimulating factor (GM-CSF) is defective, although basal levels of these transcripts are unaltered.
Journal ArticleDOI
Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB
TL;DR: The compelling evidence that NF-κB is dysregulated in many forms of cancer and that its inhibition is a logical therapy for certain cancers and for adjuvant approaches to cancer therapy is described.