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25 years of Nf-κB revIewInflammation meets cancer, with NF-κB as the matchmaker

Yinon Ben-Neriah1 & Michael Karin2

© 2011 Nature America, Inc. All rights reserved

.Inflammation is a fundamental protective response that sometimes goes awry and becomes a major cofactor in the pathogenesis of many chronic human diseases, including cancer. Here we review the evolutionary relationship and opposing functions of the transcription factor NF-kB in inflammation and cancer. Although it seems to fulfill a distinctly tumor-promoting role in many types of cancer, NF-kB has a confounding role in certain tumors. Understanding the activity and function of NF-kB in the context of tumorigenesis is critical for its successful taming, an important challenge for modern cancer biology.In 1863, Rudolf Virchow, the founder of modern pathology, noted leukocytes in neoplastic tissues and made a connection between inflammation and cancer. He suggested that the “lymphoreticular infiltrate” reflected the origin of cancer at sites of chronic irritation. In the dawn of the 20th century, Katsusaburo Yamagiwa showed that repeated painting of coal tar onto rabbits’ ears causes carcinomas. Later, in the 1940s, using repeated application of tar or croton oil onto the skin, Peyton Rous and Isaac Berenblum introduced the concept of tumor promotion, a pathogenic process distinct from tumor initiation. The early studies of Yamagiwa on the pathogen-esis of gastric carcinoma led to his belief that chronic gastric ulcers have a major role in the development of stomach cancer. In 1911, he established principles that later led him to uphold the irritation theory of cancer. Seventy years later, Barry Marshall and Robin

Warren proved that gastritis is caused by infection with Helicobacter pylori, now thought to be a major cause of many stomach cancers. Although those classical studies pointed to an association between inflammation and cancer, the mechanistic basis of this relationship emerged subsequently, with the transcription factor NF-κB serv-ing as the major lynchpin. Here we review the function of NF-κB in linking inflammation to cancer. However, rather than provid-ing a detailed summary of the inflammation-cancer connection, this review is focused on certain outstanding issues, such as the relationship between NF-κB activation and abnormal growth sig-naling, the interaction between the positive and negative roles of NF-κB in the control of inflammatory responses and how these opposing functions affect tumor development and progression. More extensive reviews of the inflammation-cancer field have been 1–5published elsewhere.

1Lautenberg Center for Immunology, Institute for Medical Research-Israel-

2Laboratory of Gene Regulation and Signal Transduction, Department of Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Pharmacology and Cancer Center, School of Medicine, University of California,

San Diego, La Jolla, California, USA. Correspondence should be addressed to

Y.B.-N. (yinon@cc.huji.ac.il) or M.K. (karinoffice@ucsd.edu).

Published online 19 July 2011; doi:10.1038/ni.2060Evolutionary linkage of NF-kB and abnormal growthInflammation is a manifestation of innate immunity, a fundamental protective response that is conserved in all multicellular animals6. The emergence of multicellular life forms required new means for defending these slow-growing organisms from rapidly growing invad-ing pathogens and for preventing the fusion of genetically distinct conspecific organisms7. Shortly after the discovery of NF-κB, it was postulated that it ‘plays the first violin’, if it is not the ‘conductor’ of inflammatory responses8,9. Although inflammation can be induced in the absence of NF-κB10, that is rarely a physiological occurrence, which possibly reflects the need for the transcription factor not only for amplification and maintenance of inflammation but also for ‘tun-ing down’ and curtailing inflammation, to preserve tissue function once the inflammation is no longer needed11.The innate immune system is well suited for detecting pathogens and foreign bodies and reacts to them by producing and releasing immune effectors and activated cells that either contain or eliminate the pathogen. An intricate signaling system composed of sensors, signal-processing and signal-transducing elements, and myriad effector molecules, from reactive oxygen species (ROS) and antibacterial pep- tides to diffusible regulators of immunity (cytokines and chemokines) was constructed for that purpose through evolution. The basic innate immunity scheme is remarkably well conserved both structurally and functionally. Thus, the main classes of pathogen sensors, Nod-like receptors and Toll-like receptors (TLRs) and interleukin 1 (IL-1) receptors, as well as the signal transducers and amplifiers IRAK, MyD88, TRAF and IKK and the transcriptional regulator Rel (NF-κB), are present even in the most primitive metazoans, sponges, sea anemones, hydra and jelly fish12–15. Notably, the RIG-I-like recep-tor family, another major arm of innate immunity that controls viral infection through the interferon response, originated much later than Nod-like receptors and TLRs, possibly only in vertebrates16.Given its considerable conservation noted above, innate immunity can be considered a hallmark of multicellularity, one of the following six essential principles of metazoan life: regulated cell replication and growth; programmed cell death; cell-cell and cell-matrix adhesion; regulated developmental processes; cell type specialization; and alloreactivity and

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innate immunity17. Although NF-κB and inflammation are commonly associated with the last principle, in fact all the principles noted above are affected by NF-κB: it contributes to induction of proliferative genes18,19; it regulates genes encoding antiapoptotic molecules20; it controls the expres-sion of diverse adhesion molecules21,22; it drives and supports develop-mental processes from lymphocyte differentiation to mammary gland development23,24; and it even has a role in cell specialization, as in driving Schwann cells to myelinate25.As many of those diverse functions go awry in tumorigenesis, it is interesting to trace the evolutionary origin of the inflammation-cancer link. Two remarkable examples are tumor promotion in Drosophila larva, in which hemocyte tumor necrosis factor (TNF) enhances tumor growth and stimulates the invasive migration of cells with mutation of the genes encoding the oncoprotein Ras and the tumor suppressor 26Scribble; likewise, leukocyte-trophic effects are needed for the pro-motion of melanoma growth in zebrafish larva27. Additional hints of a relationship between the innate response and abnormal cell growth can be found even earlier in metazoan evolution, perhaps as early as corals, which frequently develop abnormal growths resembling tumors28. In most coral specimens examined, these malformations are directly attributable to effects of predation or other physical injury. These malformations have many features in common with neoplasms, including failure of natural growth control and breakdown of the nor-mal symmetrical pattern, and overall they resemble adenomatous polyps of the human colon29,30. Deep-water corals are repeatedly preyed on by fish and other carnivores, which injure the soft parts of the coral28. This results in microbial and viral infections that trigger an inflammatory reaction that promotes regenerative proliferation and abnormal growth. Harold Dvorak described tumors as “wounds that won’t heal,” pointing to many similarities between the activity of a cancerous tumor growth and the process of wound healing31. We thus speculate that NF-κB-orchestrated innate immunity has been entwined with growth control from the early days of multicellularity. If infection is effectively controlled, then the inflammatory response is promptly resolved with no perturbation of tissue growth. Repeated infection, however, may result in tissue loss and a protracted inflam-matory response with attempt to restore the lost tissue and, thus, as in damaged corals, may end in abnormal growth.There is mounting evidence today that many tumors are propagated by means of cancer stem cells, rare cells in tumors with indefinite capacity for self-renewal32. Other tumors might arise from normal tissue stem cells or from tissue stem cells that were transformed to become cancer stem cells33,34. If that holds true, tissue stem cells should be closely guarded against infectious and chemical genotoxic insults and, at the same time, might be particularly vulnerable to deregulated innate immunity. A notable example is the close proximity of intestinal stem cells to Paneth (CD24+) cells in the small bowel and similar CD24+ cells in the colon35, the innate immune guardians of the gut epithelium. Indeed, evidence suggests that heterotypic Paneth cell–stem cell interactions have an important role in controlling stem-cell renewal35. At the far end of this innate immunity–growth control equation, abnormal growth and cancer may be found, as in the transformation of intestinal crypt stem cells into microadenomas34. Moreover, a remarkable synergy has been observed between bacte-rial infection and oncogenic mutations in Drosophila gut that drives abnormal enterocyte growth and dysplasia. Infection of Drosophila gut by Pseudomonas aeruginosa, a human opportunistic pathogen, induces intestinal damage, apoptosis and compensatory proliferation, which on a background of mutated Ras is excessive, with polarity loss, resembling a tumor36. We hypothesize that microflora-induced innate immune responses in intestinal stem cells or their niche

716?(composed mainly of CD24+ cells35), possibly in conjunction with epigenetic alterations37, may drive an abnormal proliferative response, which after further mutagenesis may generate tumor-initiating stem cells (Fig. 1).Another striking example of the equivalence of excessive innate immunity activation and abnormal growth signaling is the discovery that deletion of NFKBIA, which encodes the NF-κB inhibitor IκBα, is a rather frequent oncogenic event in glioblastoma tumors38. The occurrence of this mutation is mutually exclusive with the common glioblastoma ampli-fication of epidermal growth factor receptor (EGFR), which indicates that activation of NF-κB can replace aberrant EGF signaling as an oncogenic factor. Likewise, lung cancer cells with mutant EGFR are particularly sensitive to inhibition of NF-κB, and NF-κB activation through deletion of IκBα rescues EGFR-mutant lung cancer cells from the cytotoxic effects of the EGFR kinase inhibitor erlotinib39. Hence, whether innate immunity or a trophic control factor is deranged, the outcome could be similar; that is, abnormal growth.Pro- and anti-inflammatory functions of NF-kBSince the realization that NF-κB is an inducible rather than cell type–specific transcription factor that responds to proinflammatory cytokines and microbial products, NF-κB has been thought of as the key regulator of inflammation8. Indeed, NF-κB-binding sites have been found in the promoters of most genes encoding cytokines and chemokines40, and NF-κB activation has been shown to be essential for their induction in response to immune and inflammatory chal-lenges41. Although originally NF-κB was associated exclusively with immune and inflammatory cell function, the realization that such transcription factors also have essential roles in epithelial tissues, as in coordinating antimicrobial immunity and maintaining barrier func-tion in the gastrointestinal system, soon followed42,43. Furthermore, activated or nuclear NF-κB proteins have been detected in many chronic inflammatory conditions, including inflammatory bowel disease44,45, rheumatoid arthritis46 and psoriasis47. These diseases respond to anti-TNF therapy48, and the role of NF-κB in activating TNF transcription has been established10. Correspondingly, mouse models of inflammatory bowel disease45,49, rheumatoid arthritis9,50–52 and other inflammatory diseases respond positively to inhibitors of NF-κB, which has raised enthusiasm about NF-κB and IKKβ as thera-peutic targets in chronic inflammation and autoimmunity53. Even under acute inflammatory conditions, NF-κB is expected to have an important causal role, as genetic polymorphisms that potentiate NF-κB 54activation increase mortality due to sepsis. With that in mind, it was a big surprise and a disappointment when inhibition of NF-κB was found to increase or even cause inflammation under some cir-cumstances. One of the earliest alarming observations was greater susceptibility to chemical-induced colitis in mice lacking IKKβ in intestinal epithelial cells (IECs)55. An even more severe and sponta-neous inflammatory condition has been observed in mice devoid of IKKγ (NEMO) in IECs; these mice have an almost complete loss of NF-κB activity in these cells56. Likewise, ablation of IKKγ (NEMO) in mouse keratinocytes results in the development of a psoriasis-like inflammatory condition, which, surprisingly, is dependent on TNF57. Initially, those findings were attributed mainly to the absence of NF-κB-mediated cell-survival functions at epithelial surfaces, which serve as barriers that prevent the exposure of underlying tissue macro-phages and dendritic cells to commensal bacteria. In support of that interpretation, a variety of genes encoding molecules involved in the maintenance of epithelial layer integrity, in addition to genes encoding standard antiapoptotic molecules, have been found to be under the control of NF-κB57. However, the real ‘clincher’ was provided by studies VOLUME 12 NUMBER 8 AUGUST 2011 nature immunology© 2011 Nature America, Inc. All rights re

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Figure 1 Hypothetical model for the generation Tumor-initiating cellsof colorectal tumors as a result of interplay

among intestinal crypt microflora NF-κB

activation, and mutatagenesis mechanisms

Mutant p53Mutant APCin intestinal stem cell. Encounters of bacteria

with stem cells and their niche (composed + CD24cell–derived cytokinesmainly of Paneth-like CD24+ cells35 (granule-

filled cells)) at the bottom of the colonic Bacteriacrypts may induce activation of NF-κB in

Paneth cells and stem cells. NF-κB activation NF-κB-activated CD24+ cellresults in the release of cytokines and the

production of ROS and nitric oxide (NO), NF-κB-activated stem cellas well as the upregulation of activation-

induced cytidine deaminase (AID) in the

stem cells149, which all results in stem cell

mutagenesis. Further activation of NF-κB in

tumor-initiating cells supports their survival.

(a) A normal colonic crypt with CD24+ cells

and stem cells (thin columnar cells) at the

bottom. (b) Bacteria-loaded crypt, which

results in NF-κB activation in CD24+ cells and stem cells (red nuclei) and the release of

cytokines and enzymes. (c) NF-κB-mediated production of ROS and nitric oxide, which results in mutagenesis of the gene encoding

adenomatosis polyposis coli (APC) in an 34intestinal stem cell and adenoma growth. iNOS, inducible nitric oxide synthase.

(d) NF-κB-induced upregulation of activation-induced cytidine deaminase (AID), which results in mutagenesis of the gene encoding p53, dysplasia and invasion150, typical of colorectal cancer associated with inflammatory bowel disease151

.

abcd

© 2

011 Nature America, Inc. All rights reserved.of mice with inducible deletion of the gene encoding IKKβ (IKKβ? mice) in cells responsive to type I interferon, which include myeloid progenitors, mature myeloid cells, lymphocytes, fibroblasts and epi-thelial cells in tissues in which large amounts of type I interferon are produced. IKKβ? mice are hypersusceptible to septic shock induced by either lipopolysaccharide or bacterial infection58. Similar results have been obtained by repetitive treatment of normal mice with a specific 58IKKβ inhibitor. Even without any challenge, mice treated with an IKKβ inhibitor or IKKβ? mice develop progressive and devastating neutrophilia due to more production of IL-1β by NF-κB-deficient monocytes and macrophages59. Such experiments have shown that

in addition to its proinflammatory function, NF-κB has a direct anti-inflammatory effect; that is, inhibition of inflammasome-dependent caspase-1 activation58 (Fig. 2). Although the mechanism of inflam-masome inhibition by NF-κB is not entirely clear, it is probably related to NF-κB-induced expression of antiapoptotic proteins, such as PAI-2 and Bcl-xL (refs. 58,59). The IL-1β released by NF-κB-deficient macrophages and monocytes enhances the proliferation of granulo-cytic progenitors and increases the survival of mature neutrophils60. Although the resulting neutrophilia compensates for the loss of ?NF-κB and allows IKKβ mice to resist certain microbial infections as well as (or even better than) their wild-type counterparts, it eventu-ally results in the inflammatory destruction of tissues, which can be prevented by inhibition of IL-1β signaling60. Although such results seem to suggest that a more effective inhibition of inflammation can be achieved by combining inhibitors of IKKβ and IL-1β, it should be noted that IKKβ? mice that are also deficient in the IL-1 receptor show a complete lack of innate immunity60 and that the combined use of anti-TNF and anti-IL-1 drugs in humans results in much greater risk of infection61. Notably, IL-1β, whose production is subjected to both positive and negative controls by NF-κB, may function as a potent tumor promoter in some types of cancer62.The inflammatory response is a complex physiological host-defense system. In addition to being important for clearing foreign intruders,

nature immunology?VOLUME 12 NUMBER 8 AUGUST 2011 inflammation is important for the turnover and repair of damaged tissues. To function properly, the inflammatory response must be self-limiting and self-resolving. NF-κB orchestrates both the initiation of inflammation and its resolution11,63. In addition, part of the self-limiting nature of the inflammatory response is due to the existence of NF-κB-dependent feedback loops, such as those that entail the induc-tion of IκBα and the ubiquitin-editing enzyme A20 (ref. 64). Thus, although inhibition of NF-κB often attenuates inflammation, under somewhat different circumstance or at a different site it can aggravate or even cause inflammation. The latter outcome often becomes par-ticularly prominent under conditions of tissue injury65,66.Pro- and anti-tumorigenic roles of NF-kB in malignant cellsA potential role for NF-κB in oncogenesis was already evident in the discovery of the retroviral oncogene v-Rel as the homolog of the gene encoding c-Rel, one of the NF-κB subunits67. Subsequently, mutations in genes encoding NF-κB subunits or IκB proteins, most prominent among which were chromosomal translocations in NFKB2, were iden-tified in a variety of hematological malignancies67–70. However, the number of tumors with activated nuclear NF-κB is much larger than the subfraction of malignancies with confirmed mutations in NF-κB- or IκB-encoding genes. Such observations led to the proposal that some of the NF-κB activation seen in cancer is due to mutations that affect components of signaling pathways that activate NF-κB or is the result of exposure to inflammatory cytokines in the tumor microenvi-ronment71. Indeed, upstream mutations that cause NF-κB activation were first detected in MALT lymphomas, a group of tumors that arise through chronic antigenic stimulation of mucosal-associated lym-phoid tissue (MALT). Common MALT lymphoma mutations include chromosomal translocations that increase expression of the adaptors Bcl-10 (ref. 72) and MALT1 (ref. 73) and lead to constitutive assembly of the Carma-1–Bcl-10–MALT1 complex, whose normal function is activation of IKK–NF-κB, downstream of antigen receptors74,75. Constitutive activation of NF-κB results in greater proliferation 717

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Figure 2 Pro- and anti-inflammatory functions of NF-κB and their relationship to tumorigenesis. (a) Activation of NF-κB downstream of TNF receptors (TNFRs), TLRs and the IL-1 receptor (IL-1R) results in the induction of genes encoding prosurvival and pro-proliferative molecules,

cytokines and chemokines. The products of such genes contribute to inflammation and tumor development. However, NF-κB activation also promotes tissue integrity through the induction of genes encoding barrier molecules, protease inhibitors and antioxidants. Such molecules can suppress tumor development. By inducing the expression of antioxidant proteins, NF-κB also prevents the accumulation of pro-tumorigenic ROS and can induce DNA damage and genomic instability and lead to the activation of pro-tumorigenic transcription factors, such as STAT3 and AP-1. (b) A particularly intriguing NF-κB target gene encodes pro-IL-1β, which is processed by caspase-1 or neutrophil protease to the key proinflammatory and tumor-promoting cytokine IL-1β. Notable, while promoting pro-IL-1β expression, NF-κB negatively controls its processing to mature IL-1β through the induction of various protease inhibitors.

a

IL-1R

TNFRs

TLRs

© 2011 Nature America, Inc. All rights reserved.

Nucleus

peared. Activating mutations in (which encodes Carma-1) have been detected in activated B cell–like By analogy to B cell lymphomas in which NF-κB2 is constitutively diffuse large B cell lymphoma, another B cell malignancy76,77. Such processed as the result of its truncation because of chromosomal mutations generate constitutively active Carma-1 that associates with translocation70, multiple myeloma has been proposed to depend on the Bcl-10–MALT1 complex without antigenic stimulation, which NIK-driven NF-κB2 activation80,81. Given those expectations, it was results in persistent activation of NF-κB78. A mutation that modifies rather surprising when NIK-driven IKKβ activation turned out to the TLR adaptor MyD88 and promotes constitutive TLR signaling be more important for the survival of multiple myeloma cells than is has been found in diffuse large B cell lymphoma of the activated NIK-driven activation of IKKα87.B cell–like type. The L265P MyD88 variant promotes lymphoma cell The bulk of NF-κB-positive tumors, however, are solid malignan-survival by spontaneously assembling a protein complex containing cies derived mainly from epithelial cells. NF-κB-activating muta-the IRAK1 and IRAK4, leading to kinase activity of IRAK4, tions are extremely rare in carcinomas, although mutations and gene phosphorylation of IRAK1, signaling by NF-κB, activation of the fusions of IKKA and IKBKB have been detected through genomic

transcription factor STAT3 mediated by the kinase Jak, and secretion sequencing of breast and prostate cancer, respectively88,89. In addi-of IL-6, IL-10 and interferon-β79. Other mutations that lead to tion, the IKK-like kinase IKKε has been identified as a contributor constitutive activation of the kinase NIK and result in the activation to the malignant activity of breast carcinoma cells90. However, the

of both classical and alternative NF-κB signaling have been detected role of IKKε in the activation of NF-κB is not well established and, in multiple myeloma, another type of B cell malignancy78,80–82. therefore, its oncogenic activity may be NF-κB independent. A role Multiple myeloma–associated mutations include those in NFKB2, for IKKα in the self-renewal of breast cancer progenitors has been BTRC, CARD11, CYLD, IKBIP, IKBKB, MAP3K1, MAP3K14, RIPK4, demonstrated in a mouse model91, and IKKα has been shown to be TLR4, TNFRSF1A, BIRC2, BIRC3, TRAF2 and TRAF3. BTRC

encodes responsible for the tumor-promoting effect of progesterone in breast β-TrCP, the substrate-recognition subunit of the IκB ubiquitin cancer, which is mediated through induction of the IKKα-activating ligase83. Products of the BIRC2, BIRC3, TRAF2 and TRAF3 loci form cytokine RANKL in mammary epithelial cells92,93. IKKα activation is a ubiquitin-ligase complex responsible for degradative, Lys48-linked also important for the metastatic spread of breast cancer; this depends ubiquitination of NIK that keeps the concentration of this kinase below on the production of RANKL, which in advanced and progesterone-a critical threshold required for its autoactivation; and mutations and independent tumors is produced by tumor-infiltrating regulatory

94deletions of these genes affect this process. Other multiple myeloma– T cells rather than carcinoma cells. NF-κB activation is also involved

linked mutations have been found in NIK itself that affect the binding in the in vitro formation of breast cancer stem cells in response to acti-site for TRAF3, which connects NIK to the complex of TRAF2 and the vation of the Src tyrosine kinase95. However, the oncogenic functions ubiquitin ligases cIAP1 and cIAP2 (refs. 80,84,85). These mutations of IKKα in breast or prostate cancers96,97 are not mediated through cause the inhibition of NIK turnover, which results in its autoactiva-either classical or alternative NF-κB signaling and instead depend on tion and the subsequent phosphorylation of IKKα, the key kinase the nuclear functions of IKKα97. Notably, in the bulk of carcinomas responsible for activation of NF-κB2 processing and the generation in which classical NF-κB signaling is activated and may provide the of alternative dimers of the p52 and RelB subunits of NF-κB85,86. cancer cell with a survival advantage, the actual cause of NF-κB acti-NIK can also be overexpressed as a result of gene amplification or vation remains to be identified and is probably microenvironmental chromosomal translocations, which also occur in multiple myeloma

78. factors rather than genetic alterations.

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Pro-tumorigenic effects of NF-κB

Glioblastoma

Tumor growth promotion;amplification of EGF signaling?

Hodgkin’s disease

maintenance of supportive

microenvironment

Hepatitis-associated hepatocellular carcinoma

Anti-tumorigenic effects of NF-κ

B

Squamous cell carcinomaSuppresses Ras-induced invasive growth of epidermal tumor cells; facilitates keratinocyte senescence?

Figure 3 Pro- and anti-tumorigenic effects of NF-κB activation in cancer cells and their microenvironment. Opposing NF-κB inhibition effects are found in distinct cancer types, yet also in cancers of a similar type, depending on the mechanism of carcinogenesis. Hence, whereas NF-κB inhibition suppresses

inflammation (hepatitis)-associated liver cancer (HCC), it facilitates carcinogen-induced HCC.

Carcinogen-induced HCCPrevents cell death–associated compensatory proliferation; prevents genotoxic damage?

agents on hepatocarcinogenesis are yet to be demonstrated. On the basis of analysis of a CAC model in which tumor initiation depends on metabolic activation of the mutagen azoxymethane (AOM), it was concluded that

Colorectal cancerNF-κB activation promotes tumor develop-Attracting inflammatory cells; ment after the initiation stage, most probably inducing inflammatory cell

during early tumor promotion71,74. Although trophic and angiogenic factors

the actual tumor-initiation event in Mdr2?/?

Prostate cancer

mice is not known, NF-κB probably also acts

during the tumor-promotion stage by protect-that promote hormone-free survival of tumor cellsing premalignant cells from apoptotic elimina-tion. Another important mechanism through Multiple myeloma

which NF-κB contributes to tumor promotion

Promotes tumor cell survival,

as well as tumor progression is enhanced cell adhesion to stroma and trophic factor

supply by the microenvironmentproliferation. At least in CAC, in which this

aspect has been investigated in some detail, the

proliferative function of NF-κB is indirect and is mediated through IL-6 The role of NF-kB in the tumor microenvironment

Notably, the presence of activated NF-κB in a tumor is not necessarily and related cytokines produced by myeloid cells that lead to the activa-causal, and even when it is of importance, just like in inflammation, NF-κB tion of STAT3 in IECs55,99. Ablation of STAT3 in IECs also inhibits CAC can influence tumor development and progression both positively development, affecting both cell survival and cell proliferation99.and negatively (Fig. 3). The first two examples of a critical positive The relationships between NF-κB and STAT3 are complex (Fig. 2). role for NF-κB in linking inflammation with tumor development were In many cell types and circumstances, NF-κB and STAT3 control the colitis-associated colon cancer (CAC) and hepatitis-associated liver expression of a similar repertoire of antiapoptotic genes102,103. NF-κB cancer55,98. In CAC, a classical inflammation-driven cancer that accounts and STAT3 can both interfere with synthesis of the tumor suppres-for about 5% of sporadic colorectal cancers, it has been shown by condi-sor p53 and attenuate p53-mediated genomic surveillance104. STAT3 tional ablation of IKKβ that the activation of NF-κB in IECs, in which controls the expression of c-Myc and cyclin D103,105. Although NF-κB β-catenin signaling has been activated via mutation, provides prema-may control expression of those pro-proliferative factors in some cell lignant progenitors with a survival advantage through the induction of types, ablation of IKKβ in IECs has no effect on cell proliferation55, antiapoptotic genes, such as that encoding Bcl-xL (ref. 55). NF-κB in and in hepatocytes initiated by diethylnitrosamine (DEN), inhibition myeloid cells, most probably lamina propria macrophages, also makes of NF-κB enhances cyclin D expression and cell proliferation106. This an important contribution to tumor growth and progression through seemingly paradoxical effect is probably due to the activation of STAT3 the transcriptional activation of genes encoding growth factors that in IKKβ-depleted HCC cells107, an outcome of NF-κB inhibition that is enhance the proliferation of premalignant IECs and their transformed also observed in neutrophils60. However, in other tumor types, NF-κB derivatives55. Many inflammatory cytokines, including TNF, IL-6 and potentiates STAT3-mediated transactivation of genes encoding distinct IL-23, produced by lamina propria macrophages and dendritic cells, as inflammatory and pro-proliferative molecules in cells of the immune well as by tumor-associated macrophages, have been identified as the system present in the tumor microenvironment103. Furthermore non-main drivers of CAC growth99–101. Although TNF activates NF-κB in phosphorylated STAT3 is reported to activate the transcription of genes IECs and other epithelial cells, it should be noted that ablation of IKKβ encoding cytokines and growth-promoting molecules via NF-κB108.in myeloid cells, which prevents TNF production, does not affect NF-κB The microenvironmental functions of NF-κB are widespread and

55or the survival of premalignant IECs. Thus, the actual cause of complex. In addition to promoting the expression of inflammatory

NF-κB activation in IECs remains to be identified. TNF produced by cytokines, NF-κB seems to be involved in the polarization of tumor-activated liver inflammatory cells, however, is probably responsible for associated macrophages109. Inhibition of NF-κB in such cells converts NF-κB activation in hepatocytes of Mdr2?/? mice, which experience them from the M2 tumor-promoting phenotype to the M1 cytotoxic chronic low-grade inflammation caused by phospholipid accumula-phenotype, thereby augmenting tumor regression110. Interestingly, tion due to absence of the MDR2 phospholipid pump98. Inhibition the p50 subunit of NF-κB is a key regulator of M2-driven inflamma- of hepatocyte NF-κB through expression of a nondegradable variant tory reactions in vitro and in vivo. It has been shown that p50 inhibits

of IκBα blocks the development of hepatocellular carcinoma (HCC) NF-κB-driven M1 polarization, and p50-deficient mice have exac-in Mdr2?/? mice and enhances the apoptosis of premalignant hepato-erbated M1-driven inflammation and a defective ability to mount cytes98. Similar results have been obtained by the administration of allergy- and helminth-driven M2-polarized inflammatory reactions111. nonsteroidal anti-inflammatory drugs (NSAIDs) or anti-TNF drugs NF-κB also acts in cancer-associated fibroblasts, in which it promotes to Mdr2?/? mice98, yet the effects of long-term treatment with these the expression of a proinflammatory gene signature, important for

Promoting tumor cell survival in an inflammatory environment; inducing growth factor secretion

by inflammatory cells

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