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.

Keywords: Helicobacter pylori; NOD-like receptors; Toll-like receptors; genetic polymorphism; inflammation; pattern-recognition receptors; stomach neoplasm; therapeutics.

Figure 1

Gastric cancer classification and etiology. (A) Stomach cancer comprises gastric adenocarcinoma (GC), non-Hodgkin lymphomas, including mucosa-associated lymphoid tissue (MALT) lymphoma, and the rare gastrointestinal stromal tumors (GIST), leiomyosarcoma, and carcinoid tumors. The most common type, GC, has been classified as cardia and non-cardia GC according to anatomical location. Cardia GC is divided into two different etiological entities, esophageal-like cardia GC, which is associated with gastro-esophageal reflux, smoking, and diet, and is frequent in areas with a low risk of GC and distal stomach-like cardia GC, which is associated with the presence of H. pylori and gastric atrophy, and is the most frequent cardia GC variant in areas with a high risk of GC. Non-cardia GC is further subdivided into two histological variants called intestinal-type and diffuse-type GC. Intestinal-type GC, according to the widely accepted Correa’s cascade (7), is a biological continuum that commences as chronic gastritis and progresses to atrophic gastritis, intestinal metaplasia, dysplasia, and finally, GC. *Stomach cancer subtypes that have been associated with Helicobacter pylori infection. (B) H. pylori infection causes chronic inflammation of the gastric mucosa of all infected individuals, and in combination with host and environmental factor, leads to the development of GC in a subset of infected individuals (1–3%). In these subjects, inflammation represents the seventh hallmark of cancer and an enabling characteristic that facilitates the acquisition of the other established hallmarks that collectively dictate malignant growth (tissue invasion/metastasis, limitless replicative potential, sustained angiogenesis, evasion of programed-cell death (apoptosis), self-sufficiency in growth signals, and insensitivity to growth-inhibitory signals) (8, 9).

Figure 2

Pattern-recognition receptors involvement in Helicobacter pylori infection. H. pylori is recognized by the Toll-like receptors (TLRs) (TLR2, TLR4, TLR5, and TLR9), NOD-like receptors (NLRs) (NOD1, NOD2, NLRP3, and possibly, NLRP12 and NLRX1), RIG-I like receptors (RLRs) (RIG-I and possibly, MDA-5), and C-type lectin receptors (CLRs) (DC-SIGN). TLR4 poorly recognizes H. pylori lipopolysaccharide (LPS) to generate pro-inflammatory cytokines (e.g., IL-1α, IL-1β, IL-6, IL-8, IL-10, and TNF-α) and interferons (IFNs) through the myeloid differentiation primary response gene 88 (MyD88)-dependent and -independent pathways, respectively. TLR2 recognizes H. pylori LPS/peptigoglycan/unknown pathogen-associated molecular pattern (PAMP) while TLR5 poorly recognizes H. pylori flagella and TLR9 recognizes H. pylori DNA (unmethylated CpG motifs). H. pylori recognition by these three TLRs leads to nuclear factor-κB (NF-κB) activation. NOD1 and NOD2 recognize H. pylori peptidoglycan-derived peptides [γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP)], leading to the activation of both transcription factors NF-κB and activator protein (AP)-1. The NLRP3 inflammasome, comprising NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, recognizes a yet unknown H. pylori PAMP and/or damage-associated molecular pattern (DAMP), and through caspase-1 cleavage, leads to the maturation and secretion of interleukin (IL)-1β and IL-18. NLRX1 and NLRP12, two known negative regulators of NF-κB, appear to be significantly down-regulated during H. pylori infection in vitro, however, their exact role during H. pylori infection remains unclear. RIG-I recognizes H. pylori 5′-triphosphorylated RNA (5′-PRNA) while MDA-5 possibly recognizes H. pylori dsRNA. The dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) recognizes H. pylori fucosylated ligands and this interaction appears to counteract the pro-inflammatory immune response to H. pylori. Only one generic cell type depicting all TLRs, NLRs, RLRs, and CLRs involved in H. pylori recognition is shown here for simplicity. MAL, MyD88 adaptor-like protein, also named TIRAP; TRAM, translocating chain-associating membrane protein; TRIF, TIR domain containing adaptor inducing interferon-beta protein; TBK-1, TANK-binding kinase 1; IRF3, IFN-regulatory factor 3; TRAF6, TNF receptor-associated factor 6; IRAK, interleukin 1 receptor-associated kinase; RAS, proto-oncogene ras; c-RAF, proto-oncogene protein ras; RIP2, receptor-interacting serine/threonine-protein kinase 2, also known as RICK; CARD9, caspase activation and recruitment domain; MD-2, myeloid differentiation protein-2; ILs: interleukins. Names in orange correspond to molecules with a probable but not established role in the host response to H. pylori.

Figure 3

Pattern-recognition receptors and gastric carcinogenesis. Based on this comprehensive literature review, we propose a synergistic interaction between pattern-recognition receptors (PRRs) and Helicobacter pylori in gastric carcinogenesis. The association between PRRs and risk of GC might be a continuum commencing in childhood. Individuals harboring polymorphisms in PRRs could not only be more susceptible to acquisition of H. pylori in childhood but also would present deregulation of NF-κB in gastric epithelial and immune cells, and subsequent uncontrolled production of cytokines/chemokines, due to dysfunctional PRRs. This in turn would impact upon the direction and magnitude of the chronic inflammatory response to H. pylori. As H. pylori, the dominant bacterium in the stomach, gradually disappears upon the development of gastric atrophy, it is plausible that other microbial species might bloom in its absence and perpetuate local inflammation through further PRRs activation. Over time, the combination of these events would facilitate a number of features that promote gastric cancer development including cell proliferation, epithelial–mesenchymal transition, angiogenesis, metastasis, and immunosuppression.