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Review
, 9 (1)

NF-kappaB: Two Sides of the Same Coin

Affiliations
Review

NF-kappaB: Two Sides of the Same Coin

Bruno R B Pires et al. Genes (Basel).

Abstract

Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target.

Keywords: NF-kB; NF-kappaB; cancer; immune response; inflammation; signaling; therapy; treatment.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic overview of canonical and non-canonical Nuclear Factor-kappa B (NF-κB) pathways. EGF, epidermal growth factor; BCR, B-cell receptor; TCR, T-cell receptor; MHC, major histocompatibility complex; LPS, lipopolysaccharide; ssRNA, single-stranded RNA; dsRNA, double-stranded RNA; TNF, tumor necrosis factor; IL-1, interleukin-1; RANKL, receptor activator of nuclear factor κ-B ligand; CD40, cluster of differentiation 40; LTβR, lymphotoxin beta receptor; BAFF, B-cell activating factor; PI3K, phosphatidylinositide 3-kinase; TRAF, TNF receptor associated factor; NIK, NF-κB-inducing kinase; IκB, inhibitor of NF-κB; IKK, IκB kinase; CBP, CREB-binding protein; BCL-2, B-cell lymphoma 2; BCL-XL, B-cell lymphoma-extra large; COX-2, ciclo-oxigenase-2; NOS, nitric oxide synthase; SIP1, smad interacting protein 1 (ZEB2); MMP, Matrix metalloproteinase; P, phosphate group; Ub, ubiquitin moieties.
Figure 2
Figure 2
Immune response to tumors: (1) The loss of homeostasis driven by transformed cells will usually lead to tissue macrophage activation and an initial inflammatory response that will recruit other innate immune cells from nearby capillaries, like monocytes and Natural killer (NK) cells. After this initial phase, if the malignant cells are not cleared out, anti-inflammatory and regulatory factors, like IL-10 and TGF-β, can be secreted in order to restrain inflammation. Tumor cells can also secrete anti-inflammatory factors, rendering macrophages a tumor supportive phenotype, known as tumor associated macrophages (TAMs). (2) These anti-inflammatory factors will drive antigen presenting cells to promote a regulatory phenotype on naive T CD4+ lymphocytes (present in lymph nodes), which will restrain adaptive immunity to tumor antigens. The aim of immunotherapies nowadays is to revert this tumor permissive cycle, mainly through inhibition of receptors expressed by T cells that act as antitumor immunity silencers. In vitro co-cultures of macrophages and tumor cells not always support the role of tumor cells promoting an anti-inflammatory phenotype of macrophages. It seems that different tumors can induce different phenotypes on macrophages, even promoting its antitumor activity, through NF-κB. How these tumors escape from immune response is not well understood, but different approaches to unleash the tumor immunity are needed in this case, and also when there is no immune cell infiltration on the affected tissue.
Figure 3
Figure 3
NF-κB role on tumoral immunity: NF-κB is important for the function of both pro-inflammatory and regulatory immune cells. As such, NF-kB can have a dichotomic role on tumoral immunity depending on the type of immune cells present in the cancerous tissue. If the majority of infiltrating cells are regulatory cells, like myeloid derived suppressor cells (MDSCs) or T reg, NF-kB expression will be associated to inhibition of antitumor immune response. However, NF-kB can play a crucial role on the anti-tumor immunity driven by infiltrating inflammatory cells, supporting perforin secretion by NK cells and macrophage ability to phagocyte and eliminate tumor cells.

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