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Review
, 26 (4), 389-403

Dynamic Aberrant NF-κB Spurs Tumorigenesis: A New Model Encompassing the Microenvironment

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Review

Dynamic Aberrant NF-κB Spurs Tumorigenesis: A New Model Encompassing the Microenvironment

Spiros A Vlahopoulos et al. Cytokine Growth Factor Rev.

Abstract

Recently it was discovered that a transient activation of transcription factor NF-κB can give cells properties essential for invasiveness and cancer initiating potential. In contrast, most oncogenes to date were characterized on the basis of mutations or by their constitutive overexpression. Study of NF-κB actually leads to a far more dynamic perspective on cancer: tumors caused by diverse oncogenes apparently evolve into cancer after loss of feedback regulation for NF-κB. This event alters the cellular phenotype and the expression of hormonal mediators, modifying signals between diverse cell types in a tissue. The result is a disruption of stem cell hierarchy in the tissue, and pervasive changes in the microenvironment and immune response to the malignant cells.

Keywords: Cancer; Homeostasis; Immunity; Inflammation; Nuclear Factor kappa B.

Figures

Fig.1
Fig.1
A: depiction of the primary structure of RelA. A few representative examples of posttranslational modifications are shown. A schematic outline of relevant pathways is given in the Kyoto Encyclopedia of Genes and Genomes resource at http://www.kegg.jp/pathway/hsa04064
Fig. 2
Fig. 2
A: During inflammation, a sequential activation of different types of leukocytes takes place, induced by cytokines, chemokines, and adhesion factors. Malignant cells express subsets of genes that are normally induced in cell subtypes that are essential for survival of the organism.
Fig.3
Fig.3
A: A simplified, schematic depiction of three representative signal pathways with proven potential to interact with intracellular signal relay mechanisms regulated by NF-κB. B: STAT3 and NF-κB induce unique combinations of gene cohorts with an activity profile that can distinguish subgroups of malignant cells. C: A model drug (red arrow) that inhibits a tyrosine kinase involved in NF-κB activation (here Bruton tyrosine kinase “BTK”), will fail to work when NF-κB is constitutively active (blue arrow), and can thereby saturate regulatory sequences (promoters and enhancers) of its oncogenic targets.
Fig. 4
Fig. 4
Immune response is impaired in the vicinity of cells secreting mediators as IL-10, or prostaglandin E2, while other tissue sites, upon a local increase in e.g., IL-12, or TNFα have increased risk of cellular infiltrations and organ damage.
Fig. 5
Fig. 5
Chromatin immunoprecipitation data of the ENCODE project, for binding of transcription factors NF-κB RelA, STAT3, and c-Myc. A: on human chromosome 8q24.21 locus of the myc gene . B: On the chromosome 19q13.2, locus of the tgfb1 gene (red zone).

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