Innate immunity and hepatocarcinoma:Can toll-likereceptors open the door to oncogenesis?

Hepatocarcinoma(HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago.Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis.An effective innate immunity response relies on the tolllike receptors(TLR) found in several different liver cells which,through different ligands and many signaling pathways can elicit,not only a pro-inflammatory but also an oncogenic or anti-oncogenic response.Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets.We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015.TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNAdamages and to cell survival.However,pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis.TLR3 has a wellknown protective role influencing crucial processes like angiogenesis,cell growth or proliferation.TLR4 works as an interesting epithelial-mesenchymal transition's inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed.TLR9's influence on carcinogenesis is also controversial and despite a potential anticancer capacity,a pro-tumorigenic role is more likely.Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported.As therapeutic targets,TLRs are already in use and have a great potential.In conclusion,TLRs have been shown to be an interesting influence on the HCCs microenvironment,with TLR3 clearly determining an antitumour influence.TLR4 and TLR9 are considered to have a positive relationship with tumour development even though,in each of them anti-tumorigenic signals have been described.TLR2 presents a more ambiguous role,possibly depending on the stage of the inflammationHCC axis.

Clinical and pathological characterization of epstein-barr virus-associated gastric carcinomas in portugal

AIM To determine the prevalence of epstein-barr virus(eb V)-associated gastric carcinomas in the North Region of Portugal and to study its clinicopathological characteristics. METHODS We have performed a retrospective study including a total of 179 consecutive patients with gastric cancer(GC) submitted to gastrectomy during 2011 at the Portuguese Oncology Institute of Porto. Clinical and pathological data was collected from individual clinical records and inserted on a database with unique codification. Tumour tissues were collected from the institutional tumour bank. eb V was detected by in situ hybridization for the detection of eb V-encoded small RNAs(ebe Rs) and eb V latent proteins(LMP1 and LMP2 A) were detected by immunohistochemistry.RESULTS The analysis showed that eb V-associated gastric carcinomas(eb Va GC) represents 8.4%(15/179) of all GC cases, with a significant differential distribution among histological types(P < 0.001): 100%(3/3) of medullary carcinomas, 100%(1/1) of adenosquamous carcinoma, 8.7%(8/92) of tubular adenocarcinomas, 8.0%(2/25) of mixed carcinomas and 2%(1/51) in poorly cohesive carcinomas. The analysis revealed a higher predominance of eb Va GC in the upper third and middle(cardia, fundus and body) of the stomach(P = 0.041), a significant lower number of regional lymph nodes invasion(P = 0.025) and a tendency for better prognosis(P = 0.222). eb V latent protein expression revealed that all eb Va GC cases were LMP1-negative, nevertheless 6 cases(40%) expressed LPM2 A, which reveals that these cases show a distinct eb V-Latency profile(latency II-like).CONCLUSION eb Va GC represents 8.4% of all GC in the North Region of Portugal. The eb V-infected patients have specific clinic-pathological features that should be further explored to develop new strategies of management and treatment.

Helicobacter pylori and microRNAs:Relation with innate immunity and progression of preneoplastic conditions

The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori(H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. Micro RNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify micro RNA expression in the gastric mucosa and micro RNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. Micro RNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor micro RNAs. Furthermore, micro RNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, micro RNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each micro RNA can control the expression of hundreds to thousands of genes, knowledge of micro RNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of micro RNAs in H. pylori gastric carcinogenesis, identifying the micro RNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.

Helicobacter pylori-induced inflammation masks the underlying presence of low-grade dysplasia on gastric lesions

BACKGROUND Helicobacter pylori(H.pylori)infection has been associated with a long-term risk of precancerous gastric conditions(PGC)even after H.pylori eradication.AIM To investigate the efficacy of High-Resolution White-Light Endoscopy with Narrow-Band Imaging in detecting PGC,before/after H.pylori eradication.METHODS We studied 85 consecutive patients with H.pylori-related gastritis with/without PGC before and 6 mo after proven H.pylori eradication.Kimura-Takemoto modified and endoscopic grading of gastric intestinal metaplasia classifications,were applied to assess the endoscopic extension of atrophy and intestinal metaplasia.The histological result was considered to be the gold standard.The Sydney System,the Operative-Link on Gastritis-Assessment,and the Operative-Link on Gastric-Intestinal Metaplasia were used for defining histological gastritis,atrophy and intestinal metaplasia,whereas dysplasia was graded according to World Health Organization classification.Serum anti-parietal cell antibody and anti-intrinsic factor were measured when autoimmune atrophic gastritis was suspected.RESULTS After H.pylori eradication histological signs of mononuclear/polymorphonuclear cell infiltration and Mucosal Associated Lymphoid Tissue-hyperplasia,disappeared or decreased in 100%and 96.5%of patients respectively,whereas the Operative-Link on Gastritis-Assessment and Operative-Link on Gastric-Intestinal Metaplasia stages did not change.Low-Grade Dysplasia prevalence was similar on random biopsies before and after H.pylori eradication(17.6%vs 10.6%,P=0.19),but increased in patients with visible lesions(0%vs 22.4%,P<0.0001).At a multivariate analysis,the probability for detecting dysplasia after resolution of H.pylori-related active inflammation was higher in patients with regression or reduction of Mucosal Associated Lymphoid Tissue hyperplasia,greater alcohol consumption,and anti-parietal cell antibody and/or anti-intrinsic factor positivity[odds ratio(OR)=3.88,95%confidence interval(CI):1.31-11.49,P=0.01;OR=3.10,95%CI:1.05-9.12,P=0.04 and OR=5.47,95%CI:1.33-22.39,P<0.04,respectively].CONCLUSION High-Resolution White-Light Endoscopy with Narrow-Band Imaging allows an accurate diagnosis of Low-Grade Dysplasia on visible lesions after regression of H.pylori-induced chronic gastritis.Patients with an overlap between autoimmune/H.pylori-induced gastritis may require more extensive gastric mapping.

Toll-Like Receptors as Biomarkers of Gastric Carcinogenesis:Implications for Diagnosis,Prognosis and Treatment

Toll-like receptors (TLR) are essential for Helicobacter pylori (Hp) recognition and subsequent innate and adaptive immunity responses. TLR2 appears to be the receptor responsible for most of the immunologic reaction against Hp infection. However, TLR4, TLR9 and eventually TLR5 may also have a synergic effect with TLR2 against Hp. It has been shown that gastric Hp infection increases TLR expression in the gastric mucosa. Moreover, recent studies have shown that human gastric carcinogenesis is associated not only with increased expression of TLR but also with decreased expression of their inhibitors such as Toll-Interacting Protein (TOLLIP) and peroxisome proliferator-activated receptor (PPAR)-g. Indeed, gastric dysplasia and adenocarcinoma are associated with high expression levels of TLR and low levels of TOLLIP and PPAR-g, suggesting increased activation of these receptors throughout human gastric carcinogenesis. In this article we discuss how these novels findings could be used not only for the diagnosis and prognosis of gastric lesions associated with Hp infection but also for their treatment. Specifically, we discuss the potential use of TLR agonists in addition to antibiotics to improve eradication rates of Hp and of TLR antagonists to slow the progression of gastric preneoplastic lesions. We also discuss the potential value of TLR signalling blockers and quantification of tumoral TLR expression, respectively, in the treatment and prognosis of gastric cancer. In conclusion, TLRs can be an important link between Hp and the sequence of gastric carcinogenesis and they can be used as biomarkers of gastric carcinogenesis. In this article, future lines of investigation related with these novel scientific findings are proposed and discussed.