NF-κB, inflammation, immunity and cancer: coming of age

Key Points

  • Inflammation has been recognized as a hallmark of cancer and is known to play an essential role in the development and progression of most cancers, even those without obvious signs of inflammation and infection.

  • Nuclear factor-κB (NF-κB), a transcription factor that is essential for inflammatory responses, is one of the most important molecules linking chronic inflammation to cancer, and its activity is tightly regulated by several mechanisms.

  • Activation of NF-κB is primarily initiated by bacterial endotoxins such as lipopolysaccharide and pro-inflammatory cytokines such as tumour necrosis factor and IL-1. NF-κB activation occurs in cancer cells and in the tumour microenvironments of most solid cancers and haematopoietic malignancies.

  • NF-κB activation induces various target genes, such as pro-proliferative and anti-apoptotic genes, and NF-κB signalling crosstalk affects many signalling pathways, including those involving STAT3, AP1, interferon regulatory factors, NRF2, Notch, WNT–β-catenin and p53.

  • All known hallmarks of cancer involve NF-κB activation. In addition to enhancing cancer cell proliferation and survival, NF-κB and inflammation promote genetic and epigenetic alterations, cellular metabolic changes, the acquisition of cancer stem cell properties, epithelial-to-mesenchymal transition, invasion, angiogenesis, metastasis, therapy resistance and the suppression of antitumour immunity.

  • The prevalence of NF-κB activation in cancer-related inflammation makes it an attractive therapeutic target with the potential for minimal side effects.

Abstract

Fourteen years have passed since nuclear factor-κB (NF-κB) was first shown to serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. The young field of inflammation and cancer has now come of age, and inflammation has been recognized by the broad cancer research community as a hallmark and cause of cancer. Here, we discuss how the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity.

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Figure 1: Roles of NF-κB in cancer.
Figure 2: The two NF-κB signalling pathways.
Figure 3: Mode of action of cytokines on cancer and immune cells.
Figure 4: Chronic inflammatory crosstalk between cancer cells and immune cells.

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Acknowledgements

The authors thank S. Grivennikov (Fox Chase Cancer Center) for his comments. This work was supported by a Postdoctoral Fellowship for Research Abroad and Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science (JSPS), the Uehara Memorial Foundation Fellowship, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Kanae Foundation for the Promotion of Medical Science, JSPS KAKENHI (JP15K21775), the 'Kibou' Projects, the Astellas Foundation for Research on Metabolic Disorders, the SENSHIN Medical Research Foundation, a grant from Bristol-Myers Squibb, the SGH foundation, the MSD Life Science Foundation, the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, the Yasuda Medical Foundation, the Suzuken Memorial Foundation, the Pancreas Research Foundation of Japan, the Waksman Foundation of Japan Inc., the Japanese Foundation for Multidisciplinary Treatment of Cancer, the Toray Science Foundation, Project Mirai Cancer Research Grants from the Japan Cancer Society, a Research Grant of the Princess Takamatsu Cancer Research Fund and the Takeda Science Foundation (all to K.T.) as well as by the US National Institutes of Health (AI043477, CA219119, CA155120 and CA118165) to M.K., who is an American Cancer Society Research Professor and holder of the Benjamin G. and Wanda L. Hildyard Chair for Mitochondrial and Metabolic Diseases.

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K.T. contributed to the writing of the manuscript, and K.T. and M.K. contributed to the reviewing and editing of the manuscript.

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Correspondence to Koji Taniguchi or Michael Karin.

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Taniguchi, K., Karin, M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 18, 309–324 (2018). https://doi.org/10.1038/nri.2017.142

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