Pattern-Recognition Receptors and Gastric Cancer

Abstract

Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.

Toll-like receptor 2: An important immunomodulatory molecule during Helicobacter pylori infection

“…There are some reports indicating that both TLR4 and TLR2 contribute in the early immune response against H. pylori, leading to the secretion of cytokines [31,32].…”

“…nucleotide polymorphisms (SNPs) in the genes encoding TLR (such as TLR2 gene) showed an association with H. pylori-related gastrointestinal disorders [32,107]. The human TLR2 gene is placed on the long arm of chromosome 4 that possesses three exons including two 5ˊnon-coding exons and then after a third coding exon [108].…”

Systems-wide analyses of mucosal immune responses toHelicobacter pyloriat the interface between pathogenicity and symbiosis

“…31 The importance of the host's immune response in delineating the outcome of chronic H. pylori infection is reflected in the association of genetic polymorphisms with a higher risk for developing gastric cancer. These include IL-1b, 32 genes involved in Toll like receptor (TLR) and NOD-like receptor (NLR) signaling pathways 33,34 and the immunoregulatory transciption factor peroxisome proliferator activated receptor g (PPAR-g). 35 The relevance of these host factors will become apparent in the following sections discussing the current knowledge on innate and adaptive immune responses to H. pylori and how its virulence factors influence these processes.…”

Role ofHelicobacter pyloriinfection in pathogenesis of gastric carcinoma

“…Studies concluded that polymorphism of IL17F was involved in suscepti bility to GC [87] . Current evidences support that TLRs are play roles in both recognition of H. pylori and gastric carcinogenesis, and polymorphisms in genes involved in the TLR signaling pathways modulate the risk of GC [88] . Additionally, peroxisome proliferatoractivated receptors may play roles in H. pylori-related gastric carcinogenesis [89] .…”