Clinical Significance of Toll-like Receptor 3, 4, and 9 in Gastric Cancer

Fernández-García, Belén; Eiró, Noemí; González-Reyes, Salomé; González, Lucía; Aguirre, Alina; González, Luis O.; Casar, José M. del; García-Muñiz, José L.; Vizoso, F

doi:10.1097/cji.0000000000000016

Cited by 37 publications

(36 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TLR3 activation stimulates IL-8 release in HT-29 cells [32] in a nucleotide dependent manner (manuscript in preparation). In addition, TLR3 was found to be involved in different cancers [53, 54] and was also reported to affect intestinal inflammation in a complex manner depending on the conditions, either protecting from inflammation or causing epithelial destruction [55–59]. …”

Section: Resultsmentioning

confidence: 99%

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

Bahrami

Kukulski

Lecka

et al. 2014

Mediators of Inflammation

View full text Add to dashboard Cite

Interleukin-8 (IL-8) plays key roles in both chronic inflammatory diseases and tumor modulation. We previously observed that IL-8 secretion and function can be modulated by nucleotide (P2) receptors. Here we investigated whether IL-8 release by intestinal epithelial HT-29 cells, a cancer cell line, is modulated by extracellular nucleotide metabolism. We first identified that HT-29 cells regulated adenosine and adenine nucleotide concentration at their surface by the expression of the ectoenzymes NTPDase2, ecto-5′-nucleotidase, and adenylate kinase. The expression of the ectoenzymes was evaluated by RT-PCR, qPCR, and immunoblotting, and their activity was analyzed by RP-HPLC of the products and by detection of Pi produced from the hydrolysis of ATP, ADP, and AMP. In response to poly (I:C), with or without ATP and/or ADP, HT-29 cells released IL-8 and this secretion was modulated by the presence of NTPDase2 and adenylate kinase. Taken together, these results demonstrate the presence of 3 ectoenzymes at the surface of HT-29 cells that control nucleotide levels and adenosine production (NTPDase2, ecto-5′-nucleotidase and adenylate kinase) and that P2 receptor-mediated signaling controls IL-8 release in HT-29 cells which is modulated by the presence of NTPDase2 and adenylate kinase.

show abstract

Section: Resultsmentioning

confidence: 99%

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

Bahrami

Kukulski

Lecka

et al. 2014

Mediators of Inflammation

View full text Add to dashboard Cite

show abstract

“…In addition, these authors showed a significant trend for decrease in TOLLIP and PPARγ, two TLR signaling pathway inhibitors, which was associated with increasing levels of CDX-2, a marker for adenocarcinoma, from normal mucosa to carcinoma ( P -value <0.05) (128). Fernandez-Garcia et al (129) have also reported increased expression of TLR3, TLR4, and TLR9 in GC, and furthermore, these authors noted that TLR3 expression by cancer cells was significantly associated with a poor overall survival in patients with resectable tumors, which lead them to suggest that TLR3 might be an indicator of tumor aggressiveness. Similarly, Yakut et al (130) investigating the association between serum IL-1β, TLR4 levels, pepsinogen I and II, gastrin 17, vascular endothelial growth factor, and H. pylori CagA status in patients with a range of gastric precancerous lesions, concluded that serum TLR4 levels could be used as a biomarker to differentiate individuals presenting with dysplasia from those with other gastric precancerous lesions, the mean TLR4 level in patients with dysplasia (0.56 ± 0.098 ng/mL) being significantly higher than in patients with H. pylori positive chronic non-atrophic gastritis (0.10 ± 0.15 ng/mL), chronic atrophic gastritis (0.06 ± 0.07 ng/mL), and intestinal metaplasia (0.12 ± 0.18 ng/mL).…”

Section: Toll-like Receptors and Helicobacter Pylori-related Gastric mentioning

confidence: 95%

Pattern-Recognition Receptors and Gastric Cancer

2014

View full text Add to dashboard Cite

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.

show abstract

“…In gastric cancer, high expression of TLR3 has been shown to associate with poor prognosis. 16 Similarly, in esophageal squamous cell carcinoma increased TLR3 expression associated with occurrence of lymph node metastases. 9 Accordingly, the role of TLR3 as a prognostic factor in different types of carcinoma seems to be inconstant, and could be related both with characteristics of the local microbiome and the epithelial cell type.…”

Section: Discussionmentioning

confidence: 99%

Nucleic acid-sensing toll-like receptors 3, 7 and 8 in esophageal epithelium, barrett’s esophagus, dysplasia and adenocarcinoma

et al. 2016

View full text Add to dashboard Cite

Toll-like receptors (TLRs) are immunological receptors recognizing various microbial and endogenous ligands, such as DNA, RNA, and other microbial and host components thus activating immunological responses. The expression of TLRs in esophageal adenocarcinoma is not well known. The aim of this study was to evaluate expression patterns of those TLRs that sense nucleic acids in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinoma. TLRs 3, 7 and 8 were stained immunohistochemically and evaluated in a cohort of patients with esophageal adenocarcinoma or dysplasia. Specimens with normal esophagus (n D 88), gastric (n D 67) or intestinal metaplasia (n D 51) without dysplasia, and low-grade (n D 42) or high-grade dysplasia (n D 37) and esophageal adenocarcinoma (n D 99) were studied. We used immunofluorescence to confirm the subcellular localization of TLRs. We found abundant expression of TLR3, 7 and 8 in esophageal squamous epithelium, columnar metaplasia, dysplasia and adenocarcinoma. Cytoplasmic expression of TLR3, TLR7 or TLR8 did not associate to clinicopathological parameters or prognosis in esophageal cancer. High nuclear expression of TLR8, confirmed with immunofluorescence, in cancer cells was observed in tumors of high T-stage (p < 0.01) and in tumors with organ metastasis (p < 0.001). High nuclear TLR8 expression was associated with poor prognosis (p < 0.001). The expression of TLR3, TLR7 and TLR8 increased toward dysplasia and adenocarcinoma. We demonstrated nuclear localization of TLR8, which associates with metastasis and poor prognosis. TLR3 and TLR7 do not seem to have prognostic significance in esophageal adenocarcinoma.

show abstract

Clinical Significance of Toll-like Receptor 3, 4, and 9 in Gastric Cancer

Cited by 37 publications

References 39 publications

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

Pattern-Recognition Receptors and Gastric Cancer

Nucleic acid-sensing toll-like receptors 3, 7 and 8 in esophageal epithelium, barrett’s esophagus, dysplasia and adenocarcinoma

Contact Info

Product

Resources

About