Chronic inflammation has been suspected to be an important cause of tumour development. Nuclear factor-κB (NF-κB) activation can contribute to inflammation and tumorigenesis during tumour promotion and progression.
In several animal models of inflammation-associated cancer, NF-κB activation prevents the apoptosis of cells that are destined to become tumorigenic by upregulating the expression of anti-apoptotic genes, such as those encoding BCL-XL (B-cell lymphoma XL), BFL1 (a BCL-2-related protein) and GADD45β (growth arrest and DNA-damage-inducible 45β).
In myeloid cells, NF-κB activation leads to the transcription of genes encoding growth and survival factors that can promote the proliferation of tumour cells.
In a chemically induced model of liver cancer, inhibition of NF-κB activation leads to increased tumour growth, through increased initial death of hepatocytes and increased compensatory proliferation, which is promoted by adjacent Kupffer cells.
Serine proteases and other factors that are released by necrotic cells seem to be important stimulators of inflammatory cells, which in turn promote tumour growth.
Tumour-necrosis factor and interleukin-6 are important mediators during inflammation and tumour promotion, leading to activation of NF-κB and thereby suppression of cell death and stimulation of cell proliferation.
Inhibition of NF-κB during cancer therapy could be a useful strategy, because it would be effective in different cell types. In malignant cells, inhibition would increase susceptibility to apoptosis-inducing agents, and in inflammatory cells, it would inhibit the expression of growth and survival factors.
There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that ∼15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-κB (NF-κB) by the classical, IKK-β (inhibitor-of-NF-κB kinase-β)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.
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The authors thank J. Jenkins for help with manuscript preparation.
The authors declare no competing financial interests.
- TUMOUR-SUPPRESSOR GENE
A gene that limits the generation of cancer. Many of these genes encode proteins that regulate scheduled entry to the cell cycle or promote apoptosis of damaged cells. Loss-of-function mutations in such genes increase susceptibility to cancer.
Proto-oncogenes encode proteins that are usually involved in the control of cell growth and division. When proto-oncogenes mutate to produce proteins with increased activity, or when their concentration is increased as a consequence of gene amplification, these genes become oncogenes.
- NON-STEROIDAL ANTI-INFLAMMATORY DRUG
A drug that suppresses inflammation in a manner that is similar to that of steroids but that has a chemical structure and side-effects that are different from those of steroids. These drugs usually inhibit cyclooxygenase-2.
- TUMOUR-ASSOCIATED MACROPHAGE
An important component of the tumour microenvironment. These cells differentiate from circulating blood monocytes that have infiltrated tumours. These cells can have positive or negative effects on tumorigenesis (that is, tumour promotion or immunosurveillance, respectively).
- MDR2-KNOCKOUT MOUSE
Owing to disruption of the gene encoding MDR2 (multidrug resistance 2; also known as P-glycoprotein), this mouse strain is characterized by cholangitis and cholestatic hepatitis, leading to hepatocellular carcinoma.
- TWO-STAGE SKIN CARCINOGENESIS
A mouse model of skin cancer using 7,12-dimethylbenz(a)-anthracene (DMBA) for initiation and 12-O-tetradecanoyl phorbol 13-acetate (TPA) as a tumour promoter.
- FAMILIAL ADENOMATOUS POLYPOSIS
A genetic syndrome in which individuals are pre-disposed to developing colon cancer. It is caused by mutations in the adenomatous polyposis coli (APC) gene, and it is inherited in an autosomal dominant manner. This syndrome usually leads to the development of more than 100 colorectal adenomas, which eventually become malignant.
The initiation of a CD8+ T-cell response to an antigen that is not present in antigen-presenting cells. The antigen needs to be taken up by antigen-presenting cells and then re-routed to the MHC class I presentation pathway.
The transformation of one mature, differentiated cell type into another mature, differentiated cell type as an adaptive response to insult or injury.
A pre-neoplastic condition that often arises as a result of metaplasia. It is associated with an increased cell number and nuclear abnormalities such as hyperchromatism (a staining characteristic) and pleiomorphism (altered nuclear size and shape).
The gene that encodes p53, a tumour-suppressor protein that is found to be mutated in ∼50% of all cancers in humans. The p53 protein is a transcription factor that is activated by damage to DNA, anoxia, expression of certain oncogenes and several other stress stimuli. Target genes that are activated by p53 regulate cell-cycle arrest, apoptosis, cell senescence and DNA repair.
The generation of tumour variants with reduced immunogenicity. These might therefore escape from immune responses.
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Karin, M., Greten, F. NF-κB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5, 749–759 (2005). https://doi.org/10.1038/nri1703
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