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.
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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Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
Fujiki, H. Gist of Dr. Katsusaburo Yamagiwa's papers entitled “Experimental study on the pathogenesis of epithelial tumors” (I to VI reports). Cancer Sci. 105, 143–149 (2014).
Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).
Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004). References 4 and 5 are the first reports to identify NF-κB as a central player that links inflammation to cancer.
Kuper, H., Adami, H. O. & Trichopoulos, D. Infections as a major preventable cause of human cancer. J. Intern. Med. 248, 171–183 (2000).
Plummer, M. et al. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob. Health 4, e609–e616 (2016).
Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010). Reference 8 is an excellent comprehensive review that describes the roles of inflammation and immunity in cancer.
Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).
Shalapour, S. & Karin, M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J. Clin. Invest. 125, 3347–3355 (2015).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). This review describes the ten hallmarks of cancer.
Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016). This review describes how inflammation regulates tissue regeneration.
Sen, R. & Baltimore, D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46, 705–716 (1986).
Zhang, Q., Lenardo, M. J. & Baltimore, D. 30 Years of NF-κB: a blossoming of relevance to human pathobiology. Cell 168, 37–57 (2017).
Karin, M. Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006).
Perkins, N. D. The diverse and complex roles of NF-κB subunits in cancer. Nat. Rev. Cancer 12, 121–132 (2012).
Karin, M. & Greten, F. R. NF-κB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5, 749–759 (2005).
Staudt, L. M. Oncogenic activation of NF-κB. Cold Spring Harb. Perspect. Biol. 2, a000109 (2010).
Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol. 12, 715–723 (2011).
DiDonato, J. A., Mercurio, F. & Karin, M. NF-κB and the link between inflammation and cancer. Immunol. Rev. 246, 379–400 (2012).
Terzic, J., Grivennikov, S., Karin, E. & Karin, M. Inflammation and colon cancer. Gastroenterology 138, 2101–2114 (2010).
Lasry, A., Zinger, A. & Ben-Neriah, Y. Inflammatory networks underlying colorectal cancer. Nat. Immunol. 17, 230–240 (2016).
West, N. R., McCuaig, S., Franchini, F. & Powrie, F. Emerging cytokine networks in colorectal cancer. Nat. Rev. Immunol. 15, 615–629 (2015). References 22 and 23 are excellent Reviews that describe the roles of inflammation and cytokines in colorectal cancer.
Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).
Wang, K. et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 41, 1052–1063 (2014). References 24 and 25 reveal how 'tumour-elicited inflammation' is induced and promotes tumorigenesis in spontaneous colorectal cancer.
Schwitalla, S. et al. Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors. Cancer Cell 23, 93–106 (2013). This study shows that loss of p53 in IECs results in NF-κB activation.
Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).
Sun, S. C. The non-canonical NF-κB pathway in immunity and inflammation. Nat. Rev. Immunol. 17, 545–558 (2017).
Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004).
Vallabhapurapu, S. et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nat. Immunol. 9, 1364–1370 (2008).
Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001).
Grivennikov, S. I. & Karin, M. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21, 11–19 (2010).
Oeckinghaus, A., Hayden, M. S. & Ghosh, S. Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12, 695–708 (2011).
Zhong, B., Tien, P. & Shu, H. B. Innate immune responses: crosstalk of signaling and regulation of gene transcription. Virology 352, 14–21 (2006).
Ruland, J. Return to homeostasis: downregulation of NF-κB responses. Nat. Immunol. 12, 709–714 (2011).
Luo, J. L., Kamata, H. & Karin, M. IKK/NF-κB signaling: balancing life and death — a new approach to cancer therapy. J. Clin. Invest. 115, 2625–2632 (2005).
Xu, G. et al. Crystal structure of inhibitor of κB kinase β. Nature 472, 325–330 (2011).
Rothwarf, D. M. & Karin, M. The NF-κB activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE 1999, RE1 (1999).
Chen, Z. J. Ubiquitination in signaling to and activation of IKK. Immunol. Rev. 246, 95–106 (2012).
Tokunaga, F. & Iwai, K. LUBAC, a novel ubiquitin ligase for linear ubiquitination, is crucial for inflammation and immune responses. Microbes Infect. 14, 563–572 (2012).
Ma, X., Becker Buscaglia, L. E., Barker, J. R. & Li, Y. MicroRNAs in NF-κB signaling. J. Mol. Cell. Biol. 3, 159–166 (2011).
Boldin, M. P. & Baltimore, D. MicroRNAs, new effectors and regulators of NF-κB. Immunol. Rev. 246, 205–220 (2012).
Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA 103, 12481–12486 (2006).
Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).
Bretz, N. P. et al. Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via Toll-like receptor signaling. J. Biol. Chem. 288, 36691–36702 (2013).
Ghosh, A. et al. Telomerase directly regulates NF-κB-dependent transcription. Nat. Cell Biol. 14, 1270–1281 (2012). This study reveals the association between telomerase and NF-κB.
Taniguchi, K., Yamachika, S., He, F. & Karin, M. p62/SQSTM1 — Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Lett. 590, 2375–2397 (2016).
Greten, F. R. et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130, 918–931 (2007).
Zhong, Z. et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016). Reference 48 reports an unanticipated role of NF-κB as a negative regulator of inflammation, and reference 49 reveals the mechanism of how NF-κB suppresses inflammation.
Atretkhany, K. N., Drutskaya, M. S., Nedospasov, S. A., Grivennikov, S. I. & Kuprash, D. V. Chemokines, cytokines and exosomes help tumors to shape inflammatory microenvironment. Pharmacol. Ther. 168, 98–112 (2016).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).
Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).
Murray, P. J. Macrophage polarization. Annu. Rev. Physiol. 79, 541–566 (2017).
Porta, C. et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB. Proc. Natl Acad. Sci. USA 106, 14978–14983 (2009).
Hagemann, T. et al. “Re-educating” tumor-associated macrophages by targeting NF-κB. J. Exp. Med. 205, 1261–1268 (2008).
Ma, Y., Shurin, G. V., Peiyuan, Z. & Shurin, M. R. Dendritic cells in the cancer microenvironment. J. Cancer 4, 36–44 (2013).
Karyampudi, L. et al. PD-1 blunts the function of ovarian tumor-infiltrating dendritic cells by inactivating NF-κB. Cancer Res. 76, 239–250 (2016).
Tu, S. et al. Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14, 408–419 (2008).
Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).
Zhou, J., Zhang, J., Lichtenheld, M. G. & Meadows, G. G. A role for NF-κB activation in perforin expression of NK cells upon IL-2 receptor signaling. J. Immunol. 169, 1319–1325 (2002).
Huang, C. et al. A novel NF-κB binding site controls human granzyme B gene transcription. J. Immunol. 176, 4173–4181 (2006).
Ward, J. P., Gubin, M. M. & Schreiber, R. D. The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv. Immunol. 130, 25–74 (2016).
Gerondakis, S. & Siebenlist, U. Roles of the NF-κB pathway in lymphocyte development and function. Cold Spring Harb. Perspect. Biol. 2, a000182 (2010).
Gerondakis, S., Fulford, T. S., Messina, N. L. & Grumont, R. J. NF-κB control of T cell development. Nat. Immunol. 15, 15–25 (2014).
Oh, H. et al. An NF-κB transcription-factor-dependent lineage-specific transcriptional program promotes regulatory T cell identity and function. Immunity 47, 450–465 (2017).
Shang, B., Liu, Y., Jiang, S. J. & Liu, Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci. Rep. 5, 15179 (2015).
Grinberg-Bleyer, Y. et al. NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer. Cell 170, 1096–1108 (2017). Reference 68 shows that REL deletion or inhibition in T reg cells potentiates anti-PD1 therapy and suppresses tumour growth.
Gerondakis, S. et al. NF-κB subunit specificity in hemopoiesis. Immunol. Rev. 246, 272–285 (2012).
Evaristo, C. et al. Cutting edge: engineering active IKKβ in T cells drives tumor rejection. J. Immunol. 196, 2933–2938 (2016).
Hopewell, E. L. et al. Lung tumor NF-κB signaling promotes T cell-mediated immune surveillance. J. Clin. Invest. 123, 2509–2522 (2013).
Giampazolias, E. et al. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nat. Cell Biol. 19, 1116–1129 (2017).
Ammirante, M., Luo, J. L., Grivennikov, S., Nedospasov, S. & Karin, M. B-Cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).
Ammirante, M. et al. An IKKα-E2F1-BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence. Genes Dev. 27, 1435–1440 (2013).
Ammirante, M., Shalapour, S., Kang, Y., Jamieson, C. A. & Karin, M. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc. Natl Acad. Sci. USA 111, 14776–14781 (2014).
Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015). This is the first report to describe IgA+ immunosuppressive plasma cells, which suppress CTL activation.
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).
Koliaraki, V., Pallangyo, C. K., Greten, F. R. & Kollias, G. Mesenchymal cells in colon cancer. Gastroenterology 152, 964–979 (2017).
Erez, N., Truitt, M., Olson, P., Arron, S. T. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010).
Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).
Pallangyo, C. K., Ziegler, P. K. & Greten, F. R. IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis. J. Exp. Med. 212, 2253–2266 (2015).
Koliaraki, V., Pasparakis, M. & Kollias, G. IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. J. Exp. Med. 212, 2235–2251 (2015).
Grivennikov, S. I. & Karin, M. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann. Rheum. Dis. 70, i104–i108 (2011).
Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer 9, 361–371 (2009). Reference 84 is an excellent comprehensive Review on the role of TNF in cancer.
Taniguchi, K. & Karin, M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin. Immunol. 26, 54–74 (2014). Reference 85 is a comprehensive review on the role of the IL-6 family of cytokines in solid malignancies.
Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516 (2007).
Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H. & Vandenabeele, P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol. Cell Biol. 15, 135–147 (2014).
Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).
Voronov, E. & Apte, R. N. IL-1 in colon inflammation, colon carcinogenesis and invasiveness of colon cancer. Cancer Microenviron 8, 187–200 (2015).
Garlanda, C., Dinarello, C. A. & Mantovani, A. The interleukin-1 family: back to the future. Immunity 39, 1003–1018 (2013).
Lu, B., Yang, M. & Wang, Q. Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy. J. Mol. Med. 94, 535–543 (2016).
Liew, F. Y., Girard, J. P. & Turnquist, H. R. Interleukin-33 in health and disease. Nat. Rev. Immunol. 16, 676–689 (2016).
Ali, S. et al. The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription. J. Immunol. 187, 1609–1616 (2011).
Choi, Y. S. et al. Nuclear IL-33 is a transcriptional regulator of NF-κB p65 and induces endothelial cell activation. Biochem. Biophys. Res. Commun. 421, 305–311 (2012).
Croxford, A. L., Kulig, P. & Becher, B. IL-12-and IL-23 in health and disease. Cytokine Growth Factor Rev. 25, 415–421 (2014).
Song, X. & Qian, Y. IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases. Cell Signal. 25, 2335–2347 (2013).
Yang, B. et al. The role of interleukin 17 in tumour proliferation, angiogenesis, and metastasis. Mediators Inflamm. 2014, 623759 (2014).
Chang, Q., Daly, L. & Bromberg, J. The IL-6 feed-forward loop: a driver of tumorigenesis. Semin. Immunol. 26, 48–53 (2014).
He, G. et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384–396 (2013).
Taniguchi, K. et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015).
Taniguchi, K. et al. YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis. Proc. Natl Acad. Sci. USA 114, 1643–1648 (2017). References 100 and 101 reveal that the SRC–YAP pathway links inflammation to tissue regeneration and plays an important role in colorectal cancer.
Tian, G., Li, J. L., Wang, D. G. & Zhou, D. Targeting IL-10 in auto-immune diseases. Cell Biochem. Biophys. 70, 37–49 (2014).
Lim, C. & Savan, R. The role of the IL-22/IL-22R1 axis in cancer. Cytokine Growth Factor Rev. 25, 257–271 (2014).
Meulmeester, E. & Ten Dijke, P. The dynamic roles of TGF-β in cancer. J. Pathol. 223, 205–218 (2011).
Richmond, A. Nf-κB, chemokine gene transcription and tumour growth. Nat. Rev. Immunol. 2, 664–674 (2002).
Chow, M. T. & Luster, A. D. Chemokines in cancer. Cancer Immunol. Res. 2, 1125–1131 (2014).
Weitzenfeld, P. & Ben-Baruch, A. The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett. 352, 36–53 (2014).
Levine, B., Mizushima, N. & Virgin, H. W. Autophagy in immunity and inflammation. Nature 469, 323–335 (2011).
White, E., Karp, C., Strohecker, A. M., Guo, Y. & Mathew, R. Role of autophagy in suppression of inflammation and cancer. Curr. Opin. Cell Biol. 22, 212–217 (2010).
Zhong, Z., Sanchez-Lopez, E. & Karin, M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. Cell 166, 288–298 (2016).
Salminen, A., Hyttinen, J. M., Kauppinen, A. & Kaarniranta, K. Context-dependent regulation of autophagy by IKK-NF-κB signaling: impact on the aging process. Int. J. Cell Biol. 2012, 849541 (2012).
Baldwin, A. S. Regulation of cell death and autophagy by IKK and NF-κB: critical mechanisms in immune function and cancer. Immunol. Rev. 246, 327–345 (2012).
Copetti, T., Bertoli, C., Dalla, E., Demarchi, F. & Schneider, C. p65/RelA modulates BECN1 transcription and autophagy. Mol. Cell. Biol. 29, 2594–2608 (2009).
Ren, J. L., Pan, J. S., Lu, Y. P., Sun, P. & Han, J. Inflammatory signaling and cellular senescence. Cell Signal. 21, 378–383 (2009).
Capece, D. et al. Cancer secretome and inflammation: the bright and the dark sides of NF-κB. Semin. Cell Dev. Biol. https://doi.org/10.1016/j.semcdb.2017.08.004 (2017).
Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).
Jing, H. & Lee, S. NF-κB in cellular senescence and cancer treatment. Mol. Cells 37, 189–195 (2014).
Chien, Y. et al. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125–2136 (2011).
Soria-Valles, C. et al. NF-κB activation impairs somatic cell reprogramming in ageing. Nat. Cell Biol. 17, 1004–1013 (2015).
Pesic, M. & Greten, F. R. Inflammation and cancer: tissue regeneration gone awry. Curr. Opin. Cell Biol. 43, 55–61 (2016).
Su, T. et al. Two-signal requirement for growth-promoting function of Yap in hepatocytes. eLife 4, e02948 (2015).
Chen, Q. et al. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev. 29, 1285–1297 (2015).
Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).
Yamada, Y., Kirillova, I., Peschon, J. J. & Fausto, N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc. Natl Acad. Sci. USA 94, 1441–1446 (1997).
Cressman, D. E. et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274, 1379–1383 (1996).
Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).
Shigdar, S. et al. Inflammation and cancer stem cells. Cancer Lett. 345, 271–278 (2014).
Tanno, T. & Matsui, W. Development and maintenance of cancer stem cells under chronic inflammation. J. Nippon Med. Sch. 78, 138–145 (2011).
Blaylock, R. L. Cancer microenvironment, inflammation and cancer stem cells: A hypothesis for a paradigm change and new targets in cancer control. Surg. Neurol. Int. 6, 92 (2015).
Vazquez-Santillan, K., Melendez-Zajgla, J., Jimenez-Hernandez, L., Martinez-Ruiz, G. & Maldonado, V. NF-κB signaling in cancer stem cells: a promising therapeutic target? Cell Oncol. 38, 327–339 (2015).
Rinkenbaugh, A. L. & Baldwin, A. S. The NF-κB pathway and cancer stem cells. Cells 5, 16 (2016).
Wu, Y. & Zhou, B. P. Inflammation: a driving force speeds cancer metastasis. Cell Cycle 8, 3267–3273 (2009).
Miao, J. W., Liu, L. J. & Huang, J. Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma. Int. J. Oncol. 45, 165–176 (2014).
Wendt, M. K., Balanis, N., Carlin, C. R. & Schiemann, W. P. STAT3 and epithelial-mesenchymal transitions in carcinomas. JAKSTAT 3, e28975 (2014).
Yamamoto, M. et al. NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype. Nat. Commun. 4, 2299 (2013).
Sun, L. et al. Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells. Stem Cells 31, 1454–1466 (2013).
Baker, R. G., Hayden, M. S. & Ghosh, S. NF-κB, inflammation, and metabolic disease. Cell Metab. 13, 11–22 (2011).
Johnson, R. F. & Perkins, N. D. Nuclear factor-κB, p53, and mitochondria: regulation of cellular metabolism and the Warburg effect. Trends Biochem. Sci. 37, 317–324 (2012).
Xia, Y., Shen, S. & Verma, I. M. NF-κB, an active player in human cancers. Cancer Immunol. Res. 2, 823–830 (2014).
Liu, J. et al. Inflammation Improves Glucose Homeostasis through IKKβ-XBP1s Interaction. Cell 167, 1052–1066 (2016).
Mauro, C. et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat. Cell Biol. 13, 1272–1279 (2011). This study shows that NF-κB plays an important role in metabolic adaptation in normal cells and in cancer cells.
Kawauchi, K. Araki, K., Tobiume, K. and Tanaka, N. p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nat. Cell Biol. 10, 611–618 (2008).
Kawauchi, K., Araki, K., Tobiume, K. & Tanaka, N. Loss of p53 enhances catalytic activity of IKKbeta through O-linked β-N-acetyl glucosamine modification. Proc. Natl Acad. Sci. USA 106, 3431–3436 (2009).
Pitot, H. C., Goldsworthy, T. & Moran, S. The natural history of carcinogenesis: implications of experimental carcinogenesis in the genesis of human cancer. J. Supramol. Struct. Cell Biochem. 17, 133–146 (1981).
Barcellos-Hoff, M. H., Lyden, D. & Wang, T. C. The evolution of the cancer niche during multistage carcinogenesis. Nat. Rev. Cancer 13, 511–518 (2013).
Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).
Joyce, D. et al. NF-κB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev. 12, 73–90 (2001).
Kiraly, O., Gong, G., Olipitz, W., Muthupalani, S. & Engelward, B. P. Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo. PLoS Genet. 11, e1004901 (2015).
Colotta, F., Allavena, P., Sica, A., Garlanda, C. & Mantovani, A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073–1081 (2009).
Ren, J., Wang, Y., Gao, Y., Mehta, S.B. & Lee, C.G. FAT10 mediates the effect of TNF-α in inducing chromosomal instability. J. Cell Sci. 124, 3665–3675 (2011).
Vento-Tormo, R. et al. NF-κB directly mediates epigenetic deregulation of common microRNAs in Epstein–Barr virus-mediated transformation of B-cells and in lymphomas. Nucleic Acids Res. 42, 11025–11039 (2014).
Nakshatri, H. et al. NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT. Cell Death Dis. 6, e1608 (2015).
Shimizu, T., Marusawa, H., Endo, Y. & Chiba, T. Inflammation-mediated genomic instability: roles of activation-induced cytidine deaminase in carcinogenesis. Cancer Sci. 103, 1201–1206 (2012).
Park, S. R. Activation-induced cytidine deaminase in B cell immunity and cancers. Immune Netw. 12, 230–239 (2012).
Seplyarskiy, V. B. et al. APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication. Genome Res. 26, 174–182 (2016).
Leonard, B. et al. The PKC/NF-κB signaling pathway induces APOBEC3B expression in multiple human cancers. Cancer Res. 75, 4538–4547 (2015).
Maruyama, W. et al. Classical NF-κB pathway is responsible for APOBEC3B expression in cancer cells. Biochem. Biophys. Res. Commun. 478, 1466–1471 (2016).
Gudkov, A. V., Gurova, K. V. & Komarova, E. A. Inflammation and p53: A Tale of Two Stresses. Genes Cancer 2, 503–516 (2011).
Joneson, T. & Bar-Sagi, D. Suppression of Ras-induced apoptosis by the Rac GTPase. Mol. Cell. Biol. 19, 5892–5901 (1999).
You, Z., Madrid, L. V., Saims, D., Sedivy, J. & Wang, C. Y. c-Myc sensitizes cells to tumor necrosis factor-mediated apoptosis by inhibiting nuclear factor κB transactivation. J. Biol. Chem. 277, 36671–36677 (2002).
Basseres, D. S., Ebbs, A., Levantini, E. & Baldwin, A. S. Requirement of the NF-κB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res. 70, 3537–3546 (2010).
Pires, B. R. et al. NF-κB Is Involved in the regulation of EMT genes in breast cancer cells. PLoS ONE 12, e0169622 (2017).
Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012).
Huber, M. A. et al. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569–581 (2004).
Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).
Huang, S., Pettaway, C. A., Uehara, H., Bucana, C. D. & Fidler, I. J. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20, 4188–4197 (2001).
Gorlach, A. & Bonello, S. The cross-talk between NF-κB and HIF-1: further evidence for a significant liaison. Biochem. J. 412, e17–19 (2008).
Gilkes, D. M. & Semenza, G. L. Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol. 9, 1623–1636 (2013).
Zhang, W. et al. HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PLoS ONE 10, e0129603 (2015).
Drabsch, Y. & ten Dijke, P. TGF-β signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev. 31, 553–568 (2012).
Kisseleva, T. et al. NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancer. J. Clin. Invest. 116, 2955–2963 (2006).
Tabruyn, S. P. & Griffioen, A. W. NF-κB: a new player in angiostatic therapy. Angiogenesis 11, 101–106 (2008).
Costa, C., Incio, J. & Soares, R. Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10, 149–166 (2007).
Spina, A. et al. HGF/c-MET axis in tumor microenvironment and metastasis formation. Biomedicines 3, 71–88 (2015).
Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004).
Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).
Bollrath, J. et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15, 91–102 (2009).
Tosolini, M. et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Th2, Treg, Th17) in patients with colorectal cancer. Cancer Res. 71, 1263–1271 (2011).
Schetter, A. J. et al. Association of inflammation-related and microRNA gene expression with cancer-specific mortality of colon adenocarcinoma. Clin. Cancer Res. 15, 5878–5887 (2009).
Hinoi, T. et al. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res. 67, 9721–9730 (2007).
Fearnhead, N. S., Britton, M. P. & Bodmer, W. F. The ABC of APC. Hum. Mol. Genet. 10, 721–733 (2001).
Ulrich, C. M., Bigler, J. & Potter, J. D. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat. Rev. Cancer 6, 130–140 (2006).
Guma, M. et al. Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation. J. Exp. Med. 208, 1889–1900 (2011).
Shaked, H. et al. Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation. Proc. Natl Acad. Sci. USA 109, 14007–14012 (2012).
Vlantis, K. et al. Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. J. Clin. Invest. 121, 2781–2793 (2011).
Myant, K. B. et al. ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 12, 761–773 (2013).
Mittal, S. & El-Serag, H. B. Epidemiology of hepatocellular carcinoma: consider the population. J. Clin. Gastroenterol. 47 (Suppl.), S2–S6 (2013).
Mauad, T. H. et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am. J. Pathol. 145, 1237–1245 (1994).
Kong, L. et al. Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice. J. Exp. Clin. Cancer Res. 35, 131 (2016).
Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008).
He, G. et al. Hepatocyte IKKbeta/NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286–297 (2010).
Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).
Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010). References 192 and 193 reveal the importance of TNF-mediated NF-κB signalling in obesity-associated HCC.
Luedde, T. et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119–132 (2007).
Kondylis, V. et al. NEMO prevents steatohepatitis and hepatocellular carcinoma by inhibiting RIPK1 kinase activity-mediated hepatocyte apoptosis. Cancer Cell 28, 582–598 (2015).
Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).
Stein, B. & Yang, M. X. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-κB and C/EBPβ. Mol. Cell. Biol. 15, 4971–4979 (1995).
Galien, R. & Garcia, T. Estrogen receptor impairs interleukin-6 expression by preventing protein binding on the NF-κB site. Nucleic Acids Res. 25, 2424–2429 (1997).
Liu, H., Liu, K. & Bodenner, D. L. Estrogen receptor inhibits interleukin-6 gene expression by disruption of nuclear factor κB transactivation. Cytokine 31, 251–257 (2005).
Wang, H. et al. Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis. Am. J. Pathol. 179, 714–724 (2011).
Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015). This study shows that constitutive activation of NF-κB in hepatocytes results in HCC development.
Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).
Haybaeck, J. et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16, 295–308 (2009).
Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011).
Deng, T., Lyon, C. J., Bergin, S., Caligiuri, M. A. & Hsueh, W. A. Obesity, inflammation, and cancer. Annu. Rev. Pathol. 11, 421–449 (2016).
Gilbert, C. A. & Slingerland, J. M. Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu. Rev. Med. 64, 45–57 (2013).
Bettermann, K., Hohensee, T. & Haybaeck, J. Steatosis and steatohepatitis: complex disorders. Int. J. Mol. Sci. 15, 9924–9944 (2014).
Weglarz, T. C., Degen, J. L. & Sandgren, E. P. Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am. J. Pathol. 157, 1963–1974 (2000).
Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).
Prabhu, L., Mundade, R., Korc, M., Loehrer, P. J. & Lu, T. Critical role of NF-κB in pancreatic cancer. Oncotarget 5, 10969–10975 (2014).
Greer, J. B. & Whitcomb, D. C. Inflammation and pancreatic cancer: an evidence-based review. Curr. Opin. Pharmacol. 9, 411–418 (2009).
Fujioka, S. et al. Function of nuclear factor κB in pancreatic cancer metastasis. Clin. Cancer Res. 9, 346–354 (2003).
Dima, S. O. et al. An exploratory study of inflammatory cytokines as prognostic biomarkers in patients with ductal pancreatic adenocarcinoma. Pancreas 41, 1001–1007 (2012).
Ling, J. et al. KrasG12D-induced IKK2/β/NF-κB activation by IL-α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 21, 105–120 (2012).
Ebrahimi, B., Tucker, S. L., Li, D., Abbruzzese, J. L. & Kurzrock, R. Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis. Cancer 101, 2727–2736 (2004).
Bellone, G. et al. Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implications for survival. Cancer Immunol. Immunother. 55, 684–698 (2006).
Bryant, K. L., Mancias, J. D., Kimmelman, A. C. & Der, C. J. KRAS: feeding pancreatic cancer proliferation. Trends Biochem. Sci. 39, 91–100 (2014).
Maniati, E. et al. Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J. Clin. Invest. 121, 4685–4699 (2011).
Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).
Khasawneh, J. et al. Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion. Proc. Natl Acad. Sci. USA 106, 3354–3359 (2009).
Li, N. et al. Loss of acinar cell IKKalpha triggers spontaneous pancreatitis in mice. J. Clin. Invest. 123, 2231–2243 (2013).
Todoric, J. A. et al. Stress activated NRF2-MDM2 cascade controls neoplastic progression in pancreas. Cancer Cell 32, 824–839 (2017).
Sfanos, K. S. & De Marzo, A. M. Prostate cancer and inflammation: the evidence. Histopathology 60, 199–215 (2012).
Rajasekhar, V. K., Studer, L., Gerald, W., Socci, N. D. & Scher, H. I. Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling. Nat. Commun. 2, 162 (2011).
Jin, R. et al. NF-κB gene signature predicts prostate cancer progression. Cancer Res. 74, 2763–2772 (2014).
Tse, B. W., Scott, K. F. & Russell, P. J. Paradoxical roles of tumour necrosis factor-alpha in prostate cancer biology. Prostate Cancer 2012, 128965 (2012).
Nguyen, D. P., Li, J. & Tewari, A. K. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU Int. 113, 986–992 (2014).
Luo, J. L. et al. Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446, 690–694 (2007).
Diamanti, M. A. et al. IKKalpha controls ATG16L1 degradation to prevent ER stress during inflammation. J. Exp. Med. 214, 423–437 (2017).
Chen, W., Li, Z., Bai, L. & Lin, Y. NF-κB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Front. Biosci. 16, 1172–1185 (2011).
Cai, Z., Tchou-Wong, K. M. & Rom, W. N. NF-κB in lung tumorigenesis. Cancers 3, 4258–4268 (2011).
Mizuno, S. et al. Chronic obstructive pulmonary disease and interstitial lung disease in patients with lung cancer. Respirology 14, 377–383 (2009).
Tang, X. et al. Nuclear factor-κB (NF-κB) is frequently expressed in lung cancer and preneoplastic lesions. Cancer 107, 2637–2646 (2006).
Takahashi, H., Ogata, H., Nishigaki, R., Broide, D. H. & Karin, M. Tobacco smoke promotes lung tumorigenesis by triggering IKKβ- and JNK1-dependent inflammation. Cancer Cell 17, 89–97 (2010).
Meylan, E. et al. Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma. Nature 462, 104–107 (2009).
Duran, A. et al. The signaling adaptor p62 is an important NF-κB mediator in tumorigenesis. Cancer Cell 13, 343–354 (2008).
Bivona, T. G. et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523–526 (2011).
Blakely, C. M. et al. NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep. 11, 98–110 (2015).
Tohme, S., Simmons, R. L. & Tsung, A. Surgery for cancer: a trigger for metastases. Cancer Res. 77, 1548–1552 (2017). This is an excellent review that explains how surgery affects cancer metastasis.
Segatto, I. et al. Surgery-induced wound response promotes stem-like and tumor-initiating features of breast cancer cells, via STAT3 signaling. Oncotarget 5, 6267–6279 (2014).
Godwin, P. et al. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Front. Oncol. 3, 120 (2013).
Wang, W., Mani, A. M. & Wu, Z. H. DNA damage-induced nuclear factor-kappa B activation and its roles in cancer progression. J. Cancer Metastasis Treat. 3, 45–49 (2017).
Korkaya, H. et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol. Cell 47, 570–584 (2012).
Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).
Peng, J. et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. 75, 5034–5045 (2015).
Wang, W., Tam, W. F., Hughes, C. C., Rath, S. & Sen, R. c-Rel is a target of pentoxifylline-mediated inhibition of T lymphocyte activation. Immunity 6, 165–174 (1997).
Lin, Y., Bai, L., Chen, W. & Xu, S. The NF-κB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin. Ther. Targets 14, 45–55 (2010).
Gurpinar, E., Grizzle, W. E. & Piazza, G. A. NSAIDs inhibit tumorigenesis, but how? Clin. Cancer Res. 20, 1104–1113 (2014).
Hsu, L. C. et al. IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ. Nat. Immunol. 12, 144–150 (2011).
Storz, P. Targeting the alternative NF-κB pathway in pancreatic cancer: a new direction for therapy? Expert Rev. Anticancer Ther. 13, 501–504 (2013).
Yu, H., Kortylewski, M. & Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 7, 41–51 (2007).
Ferguson, S. D., Srinivasan, V. M. & Heimberger, A. B. The role of STAT3 in tumor-mediated immune suppression. J. Neurooncol. 123, 385–394 (2015).
Hillmer, E. J., Zhang, H., Li, H. S. & Watowich, S. S. STAT3 signaling in immunity. Cytokine Growth Factor Rev. 31, 1–15 (2016).
Haynes, K. et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum. 65, 48–58 (2013).
Rubbert-Roth, A. et al. Malignancy rates in patients with rheumatoid arthritis treated with tocilizumab. RMD Open 2, e000213 (2016).
Winthrop, K. L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol 13, 234–243 (2017).
Wardill, H. R., Bowen, J. M. & Gibson, R. J. New pharmacotherapy options for chemotherapy-induced alimentary mucositis. Expert Opin. Biol. Ther. 14, 347–354 (2014).
Tanaka, T., Narazaki, M. & Kishimoto, T. Therapeutic targeting of the interleukin-6 receptor. Annu. Rev. Pharmacol. Toxicol. 52, 199–219 (2012).
Hoesel, B. & Schmid, J. A. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer 12, 86 (2013).
Garner, J. M. et al. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB signaling in glioblastoma cancer stem cells regulates the Notch pathway. J. Biol. Chem. 288, 26167–26176 (2013).
Hagemann, T., Biswas, S. K., Lawrence, T., Sica, A. & Lewis, C. E. Regulation of macrophage function in tumors: the multifaceted role of NF-kappaB. Blood 113, 3139–3146 (2009).
Gudkov, A. V. & Komarova, E. A. p53 and the carcinogenicity of chronic inflammation. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a026161 (2016).
Xia, Y. et al. Phosphorylation of p53 by IκB kinase 2 promotes its degradation by β-TrCP. Proc. Natl Acad. Sci. USA 106, 2629–2634 (2009).
Cooks, T. et al. Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 23, 634–646 (2013).
Pasparakis, M. Role of NF-κB in epithelial biology. Immunol. Rev. 246, 346–358 (2012).
Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).
Iwanaszko, M. & Kimmel, M. NF-κB and IRF pathways: cross-regulation on target genes promoter level. BMC Genomics 16, 307 (2015).
Wietek, C., Miggin, S. M., Jefferies, C. A. & O'Neill, L. A. Interferon regulatory factor-3-mediated activation of the interferon-sensitive response element by Toll-like receptor (TLR) 4 but not TLR3 requires the p65 subunit of NF-kappa. J. Biol. Chem. 278, 50923–50931 (2003).
Han, K. J. et al. Mechanisms of the TRIF-induced interferon-stimulated response element and NF-κB activation and apoptosis pathways. J. Biol. Chem. 279, 15652–15661 (2004).
Covert, M. W., Leung, T. H., Gaston, J. E. & Baltimore, D. Achieving stability of lipopolysaccharide-induced NF-κB activation. Science 309, 1854–1857 (2005).
Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).
Wardyn, J. D., Ponsford, A. H. & Sanderson, C. M. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem. Soc. Trans. 43, 621–626 (2015).
Buelna-Chontal, M. & Zazueta, C. Redox activation of Nrf2 and NF-κB: a double end sword? Cell Signal. 25, 2548–2557 (2013).
Kohler, U. A. et al. NF-κB/RelA and Nrf2 cooperate to maintain hepatocyte integrity and to prevent development of hepatocellular adenoma. J. Hepatol. 64, 94–102 (2016).
Umemura, A. et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935–948 (2016).
Papa, S., Zazzeroni, F., Pham, C. G., Bubici, C. & Franzoso, G. Linking JNK signaling to NF-κB: a key to survival. J. Cell Sci. 117, 5197–5208 (2004).
Sakurai, T., Maeda, S., Chang, L. & Karin, M. Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl Acad. Sci. USA 103, 10544–10551 (2006).
Ma, B. & Hottiger, M. O. Crosstalk between Wnt/β-catenin and NF-κB signaling pathway during inflammation. Front. Immunol. 7, 378 (2016).
Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).
Ang, H. L. & Tergaonkar, V. Notch and NFκB signaling pathways: Do they collaborate in normal vertebrate brain development and function? Bioessays 29, 1039–1047 (2007).
Francescone, R., Hou, V. & Grivennikov, S. I. Microbiome, inflammation, and cancer. Cancer J. 20, 181–189 (2014).
Roy, S. & Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer 17, 271–285 (2017).
Dzutsev, A. et al. Microbes and cancer. Annu. Rev. Immunol. 35, 199–228 (2017).
Dzutsev, A., Goldszmid, R. S., Viaud, S., Zitvogel, L. & Trinchieri, G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur. J. Immunol. 45, 17–31 (2015).
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science https://doi.org/10.1126/science.aan4236 (2017).
Routy, B. et al. Gut microbiome influences efficacy of PD-1 based immunotherapy against epithelial tumors. Science https://doi.org/10.1126/science.aan3706 (2017).
Yu, L. C., Wang, J. T., Wei, S. C. & Ni, Y. H. Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J. Gastrointestinal Pathophysiol. 3, 27–43 (2012).
Schwabe, R. F. & Jobin, C. The microbiome and cancer. Nat. Rev. Cancer 13, 800–812 (2013).
Vemuri, R. C., Gundamaraju, R., Shinde, T. & Eri, R. Therapeutic interventions for gut dysbiosis and related disorders in the elderly: antibiotics, probiotics or faecal microbiota transplantation? Benef Microbes 8, 179–192 (2017).
Brennan, C. A. & Garrett, W. S. Gut Microbiota, Inflammation, and Colorectal Cancer. Annu. Rev. Microbiol. 70, 395–411 (2016).
Sun, J. & Kato, I. Gut microbiota, inflammation and colorectal cancer. Genes Dis. 3, 130–143 (2016).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295–309 (2016).
Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).
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.
The authors declare no competing financial interests.
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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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