Molecular mechanisms underlying chronic inflammation-associated cancers

Abstract

Although it is now accepted that chronic inflammation plays an essential role in tumorigenesis, the underlying molecular mechanisms linking inflammation and cancer remain to be fully explored. Inflammatory mediators present in the tumor microenvironment, including cytokines and growth factors, as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS), have been implicated in the etiology of inflammation-associated cancers. Epithelial NADPH oxidase (Nox) family proteins, which generate ROS regulated by cytokines, are upregulated during chronic inflammation and cancer. ROS serve as effector molecules participating in host defense or as chemo-attractants recruiting leukocytes to wounds, thereby influencing the inflammatory reaction in damaged tissues. ROS can alter chromosomal DNA, leading to genomic instability, and may serve as signaling molecules that affect tumor cell proliferation, survival, metabolism, angiogenesis, and metastasis. Targeting Noxs and their downstream signaling components may be a promising approach to pre-empting inflammation-related malignancies.

Keywords: Cancer; Inflammation; NADPH oxidase; Reactive oxygen.

Fig. 1

Schematic view of the conserved structural features of the NADPH oxidase proteins. Each isoform contains 6 putative TM domains (white cylindrical loops), with C-terminal FAD (green) and NADPH binding domains (red). The NADPH binding domain structural models were created by the SWISS-MODEL program server with hNOX2 (PDB: 3A1F) as the template, visualized by Pymol software. (A) NOX1-4 are depicted with loop regions labeled based on established designations: extracellular loops A, C, E and intracellular loops B and D. (B) The NOX5 isoform shares the same structural motif as NOX1-4, with a novel N-terminal calcium binding region, composed of 4 EF-hand calcium binding sites (orange squares). (C) DUOX1-2 are unique to the NADPH oxidase family, as both isoforms contain an extracellular N-terminal peroxidase homology domain (orange) and two cytosolic calcium binding sites.

Fig. 2

Role of cytokines, growth factors, and Noxs in tumor initiation, promotion, and progression. Schematic representation showing cytokines and growth factors are secreted by inflammatory cells and stromal cells in the tumor microenvironment during chronic inflammation; they engage their cognate receptors to activate downstream kinases and transcription factors such as NF-κB, STAT, and HIFs. These TFs can up-regulate the expression, and enhance the activity of Noxs. They can also regulate target genes involved in cell cycle control, apoptosis, metabolism, angiogenesis, and metastasis. On the other hand, Nox-derived ROS can oxidize redox-sensitive cysteine residues in the catalytic domain of PTPs and inactivate their ability to limit the propagation of cytokine-derived signals. ROS can also directly oxidize the cysteine residues in some TFs and regulate their transcriptional activity. [PTP, protein tyrosine phosphatase; ROS, reactive oxygen species; HIFs, hypoxia-inducible factors; Noxs, NADPH oxidases].