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.
Highlights
Of the three main types of stomach cancer, gastric adenocarcinoma (GC), non-Hodgkin’s lymphoma, and gastrointestinal stromal tumors, approximately 95% are GC, which remains one of the most commonly diagnosed cancers in the world [1]
In conclusion, abundant evidence supports the pivotal role of pattern-recognition receptors (PRRs) in gastric carcinogenesis as these receptors of the innate immune system, including Toll-like receptors (TLRs), NLRs, C-type lectin receptors (CLRs), and RLRs, have been shown to recognize diverse components of H. pylori, the major risk factor of GC
PRRs are involved in gastric carcinogenesis per se as these receptors are known to exert tumor-promoting functions as well as immunosuppression during cancer
Summary
Of the three main types of stomach cancer, gastric adenocarcinoma (GC), non-Hodgkin’s lymphoma, and gastrointestinal stromal tumors, approximately 95% are GC, which remains one of the most commonly diagnosed cancers in the world [1]. Intestinal-type GC is characterized by the formation of gland-like structures, distal stomach localization, and a predilection for older individuals It is more frequent in males (2:1 ratio) and in subjects of lower socioeconomic status [10]. This type of GC is often preceded by a precancerous phase that starts with the transition of normal mucosa into multifocal atrophic gastritis. Diffuse-type GC is poorly differentiated, affects younger individuals, and has been highly associated with genetic susceptibility (the variant hereditary diffuse GC, which is associated with germ-line mutations in CDH1, a gene encoding E-cadherin) [12, 13] It is not associated with the formation of precancerous lesions and has been found to affect the www.frontiersin.org
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