Helicobacter pylori infection induces gastric precancerous lesions and persistent expression of Angpt2, Vegf-A and Tnf-A in a mouse model.

Introduction: Helicobacter pylori colonizes the gastric mucosa and induces chronic inflammation. Methods: Using a mouse model of H. pylori-induced gastritis, we evaluated the mRNA and protein expression levels of proinflammatory and proangiogenic factors, as well as the histopathological changes in gastric mucosa in response to infection. Five- to six-week-old female C57BL/6N mice were challenged with H. pylori SS1 strain. Animals were euthanized after 5-, 10-, 20-, 30-, 40- and 50-weeks post infection. mRNA and protein expression of Angpt1, Angpt2, VegfA, Tnf-α, bacterial colonization, inflammatory response and gastric lesions were evaluated. Results: A robust bacterial colonization was observed in 30 to 50 weeks-infected mice, which was accompanied by immune cell infiltration in the gastric mucosa. Compared to non-infected animals, H. pylori-colonized animals showed an upregulation in the expression of Tnf-A, Angpt2 and VegfA at the mRNA and protein levels. In contrast, Angpt1 mRNA and protein expression was downregulated in H. pylori-colonized mice. Conclusion: Our data show that H. pylori infection induces the expression of Angpt2, Tnf-A and Vegf-A in murine gastric epithelium. This may contribute to the pathogenesis of H. pylori-associated gastritis, however the significance of this should be further addressed.

Helicobacter pylori infection induces abnormal expression of pro-angiogenic gene ANGPT2 and miR-203a in AGS gastric cell line.

Helicobacter pylori colonizes the stomach and induces an inflammatory response that can develop into gastric pathologies including cancer. The infection can alter the gastric vasculature by the deregulation of angiogenic factors and microRNAs. In this study, we investigate the expression level of pro-angiogenic genes (ANGPT2, ANGPT1, receptor TEK), and microRNAs (miR-135a, miR-200a, miR-203a) predicted to regulate those genes, using H. pylori co-cultures with gastric cancer cell lines. In vitro infections of different gastric cancer cell lines with H. pylori strains were performed, and the expression of ANGPT1, ANGPT2, and TEK genes, and miR-135a, miR-200a, and miR-203a, was quantified after 24 h of infection (h.p.i.). We performed a time course experiment of H. pylori 26695 infections in AGS cells at 6 different time points (3, 6, 12, 28, 24, and 36 h.p.i.). The angiogenic response induced by supernatants of non-infected and infected cells at 24 h.p.i. was evaluated in vivo, using the chicken chorioallantoic membrane (CAM) assay. In response to infection, ANGPT2 mRNA was upregulated at 24 h.p.i, and miR-203a was downregulated in AGS cells co-cultured with different H. pylori strains. The time course of H. pylori 26695 infection in AGS cells showed a gradual decrease of miR-203a expression concomitant with an increase of ANGPT2 mRNA and protein expression. Expression of ANGPT1 and TEK mRNA or protein could not be detected in any of the infected or non-infected cells. CAM assays showed that the supernatants of AGS-infected cells with 26695 strain induced a significantly higher angiogenic and inflammatory response. Our results suggest that H. pylori could contribute to the process of carcinogenesis by downregulating miR-203a, which further promotes angiogenesis in gastric mucosa by increasing ANGPT2 expression. Further investigation is needed to elucidate the underlying molecular mechanisms.

The TNF-A-857*T Polymorphism is Associated with Gastric Adenocarcinoma Risk in a Costa Rican Population.

BACKGROUND: Costa Rica is ranked as one of the countries with highest incidence of gastric cancer worldwide. Previous studies in Costa Rican populations have revealed associations between gastric cancer risk and several cytokine polymorphisms that seem to play a role in the regulation of the expression of these proteins. In this study, we assessed associations of the polymorphisms IL-6-174 G/C, IFNGR1-56 C/T, IL-8-251 T/A and TNF-A (-857 C/T, -308 A/G) with gastric pathologies in a high-risk population of Latin America. METHODS: DNA samples of 47 patients with gastric adenocarcinoma, 53 with chronic gastritis, 56 with duodenal ulcer and 94 healthy controls, were genotyped for the five mentioned SNPs. All participants were ≥50-years-old. Genotyping was performed by PCR-RFLP and 5'-nuclease PCR assay. H. pylori infection, CagA status, pepsinogen (PG) I and II blood levels were determined by ELISA. Logistic regression analysis was used to determine possible associations of the polymorphisms with cancer, gastritis and duodenal ulcer, and linear regression analysis to determine associations with blood PG levels. RESULTS: A total of 86.6% of the population was positive for H. pylori; of them, 51.6% was CagA+. Patients with the TNF-A-857*T allele had an increased risk for gastritis (OR: 3.67, p = 0.015) and gastric adenocarcinoma (OR:6.15, p = 0.001). Associations between other polymorphisms and gastric diseases, or PG levels, were not found. CONCLUSIONS: Our results indicate that the TNF-A-857*T SNP is among the risk factors associated with the risk of gastric cancer in Costa Rica.

Helicobacter pylori Colonization Drives Urokinase Receptor (uPAR) Expression in Murine Gastric Epithelium During Early Pathogenesis.

(1) Background: Persistent Helicobacter pylori infection is the most important risk factor for gastric cancer. The urokinase receptor (uPAR) is upregulated in lesions harboring cancer invasion and inflammation. Circumstantial evidence tends to correlate H. pylori colonization with increased uPAR expression in the human gastric epithelium, but a direct causative link has not yet been established in vivo; (2) Methods: In a mouse model of H. pylori-induced gastritis, we investigated the temporal emergence of uPAR protein expression in the gastric mucosa in response to H. pylori (SS1 strain) infection; (3) Results: We observed intense uPAR immunoreactivity in foveolar epithelial cells of the gastric corpus due to de novo synthesis, compared to non-infected animals. This uPAR induction represents a very early response, but it increases progressively over time as do infiltrating immune cells. Eradication of H. pylori infection by antimicrobial therapy causes a regression of uPAR expression to its physiological baseline levels. Suppression of the inflammatory response by prostaglandin E2 treatment attenuates uPAR expression. Notwithstanding this relationship, H. pylori does induce uPAR expression in vitro in co-cultures with gastric cancer cell lines; (4) Conclusions: We showed that persistent H. pylori colonization is a necessary event for the emergence of a relatively high uPAR protein expression in murine gastric epithelial cells.

Gastric Cancer in the Era of Immune Checkpoint Blockade.

Gastric cancer (GC) is one of the most important malignancies worldwide because of its high incidence and mortality. The very low survival rates are mainly related to late diagnosis and limited treatment options. GC is the final clinical outcome of a stepwise process that starts with a chronic and sustained inflammatory reaction mounted in response to Helicobacter pylori infection. The bacterium modulates innate and adaptive immunity presumably as part of the strategies to survive, which favors the creation of an immunosuppressive microenvironment that ultimately facilitates GC progression. T-cell exhaustion, which is characterized by elevated expression of immune checkpoint (IC) proteins, is one of the most salient manifestations of immunosuppressive microenvironments. It has been consistently demonstrated that the tumor-immune microenvironment(TIME)-exhausted phenotype can be reverted by blocking ICs with monoclonal antibodies. Although these therapies are associated with long-lasting response rates, only a subset of patients derive clinical benefit, which varies according to tumor site. The search for biomarkers to predict the response to IC inhibition is a matter of intense investigation as this may contribute to maximize disease control, reduce side effects, and minimize cost. The approval of pembrolizumab for its use in GC has rocketed immuno-oncology research in this cancer type. In this review, we summarize the current knowledge centered around the immune contexture and recent findings in connection with IC inhibition in GC.

Evaluation of the expression of the oncogen C-ERBB-2/HER2 in advanced gastric cancer cases from Costa Rica.

JUSTIFICATION: The prevalence of gastric cancer (GC) with increased expression of the HER2 oncoprotein shows important variations worldwide. Incidence and mortality rates of GC in Costa Rica are among the highest in Latin America and the world; however, the prevalence of HER2-positive cases in this country is unknown. Evaluation of this parameter is important to decide the therapeutic approach for GC patients. The aim of this study was to provide an estimation of the prevalence of GC patients overexpressing the HER2 oncogene in Costa Rica. METHODS: The investigation was carried out in two phases. The first one consisted of a retrospective review of 331 clinical records of patients diagnosed with advanced or metastatic GC from January 2010 to January 2012 in four hospitals in Costa Rica. In the second phase, immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) analyses were performed in formalin-fixed and paraffin-embedded (FFPE) surgical samples from 50 patients diagnosed with GC between 2012 and 2015. RESULTS: Of the 331 clinical files reviewed, the assessment of HER2 status was carried out in 62 patients (18.7%), of which only five (8%) were HER2-positive. In the 50 surgical specimens in which IHC and FISH analyses were performed, two of them (4%) presented overexpression and amplification of the HER2 oncogene. CONCLUSION: This study suggests that the prevalence of GC cases overexpressing the HER2 oncogene in Costa Rica is less than 8%. This is the first attempt ever undertaken to estimate the prevalence of HER2-positivity in GC in Costa Rica.

Evaluation of pharmacological therapies used in Costa Rica in patients with metastatic gastric cancer: a retrospective study.

BACKGROUND: Gastric cancer is one of the leading causes of cancer death worldwide. Surgery is regarded as the best curative treatment option for gastric cancer; however, a high proportion of cases are diagnosed at advanced stages, when tumors are unresectable. In the present study, we evaluated the impact of pharmacological therapies in the survival of 168 patients diagnosed with metastatic gastric cancer from Costa Rica, a country with very high incidence and mortality rates for this malignancy. METHODS: We retrospectively reviewed 168 clinical records of patients diagnosed with metastatic gastric cancer from January 2009 to January 2012 at four major hospitals in Costa Rica. The Chi-square test or Fisher's exact test was used for comparison of frequencies, while the ANOVA test was used for comparison of quantitative variables. OS and PFS analyses were performed using the Kaplan-Meier method. The Log-rank test was used to compare survival curves. Univariate and multivariate COX regression analyses were used to calculate the crude and adjusted hazard ratios (HR) with their 95% confidence interval (95% CI). RESULTS: After a median follow-up of 46.5 months, the median survival difference between the two groups (pharmacological therapy vs. supportive care) was 5.6 months for PFS and 8.3 months for OS. Patients receiving triple therapy had 69% higher chance of progression than those receiving double therapy (HR =1.69, 95% CI: 1.04-2.73). The probability of dying is 88% higher for the patients receiving triple therapy than for those using double therapy (HR =1.88, 95% CI: 1.15-3.11). CONCLUSIONS: This study demonstrates that pharmacological therapies significantly increase the PFS and OS of those patients with metastatic gastric cancer in Costa Rica. The greatest benefit in terms of survival is observed with the use of duplets in comparison with the triplets in these patients.

Priming the seed: Helicobacter pylori alters epithelial cell invasiveness in early gastric carcinogenesis.

Helicobacter pylori (H. pylori) infection is a well-established risk factor for the development of gastric cancer (GC), one of the most common and deadliest neoplasms worldwide. H. pylori infection induces chronic inflammation in the gastric mucosa that, in the absence of treatment, may progress through a series of steps to GC. GC is only one of several clinical outcomes associated with this bacterial infection, which may be at least partially attributed to the high genetic variability of H. pylori. The biological mechanisms underlying how and under what circumstances H. pylori alters normal physiological processes remain enigmatic. A key aspect of carcinogenesis is the acquisition of traits that equip preneoplastic cells with the ability to invade. Accumulating evidence implicates H. pylori in the manipulation of cellular and molecular programs that are crucial for conferring cells with invasive capabilities. We present here an overview of the main findings about the involvement of H. pylori in the acquisition of cell invasive behavior, specifically focusing on the epithelial-to-mesenchymal transition, changes in cell polarity, and deregulation of molecules that control extracellular matrix remodeling.

Predictors of overall survival after surgery in gastric cancer patients from a Latin-American country.

BACKGROUND: Gastric cancer is one of the major causes of cancer-related deaths in several Latin-American countries, including Costa Rica. However, determinants of poor outcomes are fairly unknown for patients from this region. The aim of this study was to determine prognostic variables of overall survival (OS) in a cohort of Hispanic patients after curative-intent surgery for gastric cancer. METHODS: We retrospectively evaluated the clinical records of 236 consecutive patients who underwent surgery for advanced gastric cancer at four major hospitals in Costa Rica. Univariate and multivariate Cox proportional models were used to assess the influence of age, sex, clinical stage, adjuvant therapy, type of dissection (D1 vs. D2), extent of gastrectomy (partial vs. total), margin status (R0 vs. R1/2), tumour differentiation, and tumour location on OS. RESULTS: After a median follow-up of 46.5 months, median OS was 47.6 months [95% confidence interval (CI): 34.7-60.4]. There was no survival benefit of adjuvant chemotherapy [hazard ratio (HR): 1.18; 95% CI: 0.70-2.00; P=0.53] or postoperative chemoradiotherapy (CRT) (HR: 1.04; 95% CI: 0.71-1.52; P=0.85) compared to surgery alone. After adjustment for potential confounders, the R0 status was associated with better OS (HR: 0.51; 95% CI: 0.28-0.92; P=0.03). Similarly, clinical stage (III vs. I) (HR: 2.26; 95% CI: 1.39-4.29; P=0.001), poor differentiated (HR: 1.72; 95% CI: 1.22-2.76; P=0.03) and undifferentiated tumours (HR: 2.37; 95% CI: 1.39-4.23; P=0.001) were associated with worse outcomes. CONCLUSIONS: The surgical margin status, clinical stage, and tumour differentiation were predictor variables for OS in this cohort of gastric cancer patients.

Relevance of the plasminogen activation system in the pathogenesis and progression of gastric cancer / La importancia del sistema activador de plasminógeno en la patogénesis y progresión del cáncer gástrico

Abstract Gastric cancer is ranked as the third death-causing cancer and one of the most incident malignancies worldwide. AlthoughHelicobacter pyloriis the most well-established risk factor for the development of this neoplasm, most of the infected individuals do not develop gastric cancer. Two of the main challenges faced by the world's scientific community in the combat against gastric cancer are the unraveling of its pathogenesis and the identification of novel ways to bring down the mortality. Malignant cell invasion of the non-neoplastic adjacent tissue and metastasis are pivotal events during cancer development and progression. Both processes are facilitated by proteases capable of degrading components of the extracellular matrix, some of which have been associated to clinic-pathological aspects of the disease. Recent studies have suggested the possible connection betweenH. pyloriand the expression of some of these proteases in gastric mucosa. This review summarizes the current knowledge about epidemiological, clinical and biological aspects of gastric cancer; it also discusses the main findings about the involvement of the plasminogen activation system in the development and progression of this disease, as well as its potential repercussions in the clinical setting. Rev. Biol. Trop. 66(1): 28-47. Epub 2018 March 01.

Resumen El cáncer gástrico es la tercera causa de muerte por cáncer a nivel mundial y uno de los más incidentes. A pesar de que la infección porHelicobacter pylories el factor de riesgo más reconocido para el desarrollo de esta neoplasia, la mayoría de personas infectadas con la bacteria no desarrolla la enfermedad. Dos de los principales desafíos a los que actualmente se enfrenta la comunidad científica mundial en la lucha contra el cáncer gástrico son el esclarecimiento de la patogénesis y la identificación de nuevos parámetros que contribuyan a disminuir la mortalidad. La invasión de las células malignas al tejido no neoplásico adyacente y la metástasis son eventos claves durante el desarrollo y progresión del cáncer. Lo anterior es facilitado por proteasas capaces de degradar los componentes de la matriz extracelular, algunas de las cuales han sido asociadas con aspectos clínico-patológicos de la enfermedad. Estudios recientes han sugerido la posible relación entre la bacteriaH. pyloriy la inducción en mucosa gástrica de algunas de estas proteasas. Esta revisión resume conocimientos actuales sobre aspectos epidemiológicos, clínicos y biológicos del cáncer gástrico; también discute los principales hallazgos en torno a la participación del sistema activador de plasminógeno en el desarrollo y progresión del mismo, así como sus potenciales repercusiones en la práctica clínica.

Tissue Inhibitor of Metalloproteinase-1 Is Confined to Tumor-Associated Myofibroblasts and Is Increased With Progression in Gastric Adenocarcinoma.

The tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the extracellular matrix-degrading activity of several matrix metalloproteinases, thereby regulating cancer cell invasion and metastasis. Studies describing the expression pattern and cellular localization of TIMP-1 in gastric cancer are, however, highly discordant. We addressed these inconsistencies by performing immunohistochemistry and in situ hybridization analyses in a set of 49 gastric cancer lesions to reexamine the TIMP-1 localization. In addition, we correlated these findings to clinicopathological parameters. We show that strong expression of TIMP-1 protein and mRNA was observed in a subpopulation of stromal fibroblast-like cells at the periphery of the cancer lesions. In a few cases, a small fraction of cancer cells showed weak expression of TIMP-1 protein and mRNA. The stromal TIMP-1-expressing cells were mainly tumor-associated myofibroblasts. In the normal-appearing mucosa, scattered TIMP-1 protein was only found in chromogranin A positive cells. TIMP-1-positive myofibroblasts at the invasive front of the tumors were more frequently seen in intestinal than in diffuse histological subtype cases (p=0.009). A significant trend to a higher number of cases showing TIMP-1 staining in myofibroblasts with increasing tumor, node, metastasis (TNM) stage was also revealed (p=0.041). In conclusion, tumor-associated myofibroblasts are the main source of increased TIMP-1 expression in gastric cancer.

Tissue inhibitor of matrix metalloproteinase-1 expression in colorectal cancer liver metastases is associated with vascular structures.

Metastatic growth by colorectal cancer cells in the liver requires the ability of the cancer cells to interact with the new microenvironment. This interaction results in three histological growth patterns of liver metastases: desmoplastic, pushing, and replacement. In primary colorectal cancer several proteases, involved in the degradation of extracellular matrix components, are up-regulated. In liver metastases, their expression is growth pattern dependent. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a strong prognostic marker in plasma from colorectal cancer patients, with significant higher levels in patients with metastatic disease. We therefore wanted to determine the expression pattern of TIMP-1 in primary colorectal cancers and their matching liver metastases. TIMP-1 mRNA was primarily seen in α-smooth-muscle actin (α-SMA)-positive cells. In all primary tumors and liver metastases with desmoplastic growth pattern, TIMP-1 mRNA was primarily found in α-SMA-positive myofibroblasts located at the invasive front. Some α-SMA-positive cells with TIMP-1 mRNA were located adjacent to CD34-positive endothelial cells, identifying them as pericytes. This indicates that TIMP-1 in primary tumors and liver metastases with desmoplastic growth pattern has dual functions; being an MMP-inhibitor at the cancer periphery and involved in tumor-induced angiogenesis in the pericytes. In the liver metastases with pushing or replacement growth patterns, TIMP-1 was primarily expressed by activated hepatic stellate cells at the metastasis/liver parenchyma interface. These cells were located adjacent to CD34-positive endothelial cells, suggesting a function in tumor-induced angiogenesis. We therefore conclude that TIMP-1 expression is growth pattern dependent in colorectal cancer liver metastases.

The urokinase receptor homolog Haldisin is a novel differentiation marker of stratum granulosum in squamous epithelia.

Several members of the Ly-6/uPAR (LU)-protein domain family are differentially expressed in human squamous epithelia. In some cases, they even play important roles in maintaining skin homeostasis, as exemplified by the secreted single domain member, SLURP-1, the deficiency of which is associated with the development of palmoplantar hyperkeratosis in the congenital skin disorder Mal de Meleda. In the present study, we have characterized a new member of the LU-protein domain family, which we find to be predominantly expressed in the stratum granulosum of human skin, thus resembling the expression of SLURP-1. In accordance with its expression pattern, we denote this protein product, which is encoded by the LYPD5 gene, as Haldisin (human antigen with LU-domains expressed in skin). Two of the five human glycolipid-anchored membrane proteins with multiple LU-domains characterized so far are predominantly confined to squamous epithelia (i.e., C4.4A), to stratum spinosum, and Haldisin to stratum granulosum under normal homeostatic conditions. Whether Haldisin is a prognostic biomarker for certain epithelial malignancies, like C4.4A and SLURP-1, remains to be explored.

Prognosis in adenocarcinomas of lower oesophagus, gastro-oesophageal junction and cardia evaluated by uPAR-immunohistochemistry.

Adenocarcinomas of lower oesophagus, gastro-oesophageal junction and cardia in humans are highly invasive tumours with poor prognosis. The localisation of urokinase-type plasminogen activator receptor (uPAR) was determined in 66 patients; 60 with adenocarcinomas and six cases with Barrett's oesophagus. uPAR was expressed in nearly all cases of invasive adenocarcinomas by populations of cancer cells, macrophages and myofibroblasts at both the invasion front and the tumour core. In areas with high-grade dysplasia or with Barrett's metaplasia adjacent to the tumour tissue, no uPAR-immunoreactivity was found. High local expression of uPAR, therefore, appears to be a characteristic marker for invasive behaviour in this tumour, suggesting that uPAR's contribution to matrix degradation during invasive growth is a late event in carcinogenesis. Using a scoring system for semiquantitative estimation of uPAR-positivity on immmunohistochemically stained specimens, a significant association was found between poor overall survival and high uPAR-score for cancer cells in the tumour core and for macrophages peripherally at the tumour invasion zone. In multivariate analysis, these two uPAR-scores were confirmed as highly significant prognostic parameters independent of Tumour, Node, Metastasis (TNM)-stage and World Health Organization (WHO) classification. The proteolytic action of these malignant and nonmalignant accessory cells thus seemed to follow two main patterns: one dominated by uPAR positive cancer cells and one by uPAR-positive macrophages. Scoring of uPAR-positivity might be a useful parameter for onset of invasion and prognosis in these adenocarcinomas.

Urokinase plasminogen activator receptor on invasive cancer cells: a prognostic factor in distal gastric adenocarcinoma.

Gastric cancer is the second cancer causing death worldwide. The five-year survival for this malignancy is below 25% and few parameters have shown an impact on the prognosis of the disease. The receptor for urokinase plasminogen activator (uPAR) is involved in extracellular matrix degradation by mediating cell surface associated plasminogen activation, and its presence on gastric cancer cells is linked to micrometastasis and poor prognosis. Using immunohistochemistry, the prognostic significance of uPAR was evaluated in tissue samples from a retrospective series of 95 gastric cancer patients. uPAR was expressed by neoplastic cells, macrophages, myofibroblasts and neutrophils in both intestinal and diffuse subtypes. No association was demonstrated between the expression of uPAR on cancer cells and histological subtype (p = 0.64) or TNM stage (p = 0.75). Univariate analysis revealed a significant association between the expression of uPAR on tumor cells in the peripheral invasion zone and overall survival of gastric cancer patients (HR = 2.16; 95% CI: 1.13-4.14; p = 0.02). Multivariate analysis showed that uPAR immunoreactivity in cancer cells at the invasive front is an independent prognostic factor for overall survival in gastric cancer (HR = 2.39; 95% CI: 1.22-4.69; p = 0.011). In consequence, scoring of uPAR-positive cancer cells may be a direct measure for the invasive potential of gastric adenocarcinomas.

Urokinase plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high- and low-risk countries.

Gastric cancer is the second cancer causing death worldwide. Both incidence and mortality rates vary according to geographical regions. The receptor for urokinase plasminogen activator (uPAR) is involved in extracellular matrix degradation by mediating cell surface associated plasminogen activation, and its presence on gastric cancer cells is linked to micro-metastasis and poor prognosis. Immunohistochemical analyses of a set of 44 gastric cancer lesions from Costa Rica showed expression of uPAR in cancer cells in both intestinal subtype (14 of 27) and diffuse subtype (10 of 17). We compared the expression pattern of uPAR in gastric cancers from a high-risk country (Costa Rica) with a low-risk country (Norway). We found uPAR on gastric cancer cells in 24 of 44 cases (54%) from Costa Rica and in 13 of 23 cases (56%) from Norway. uPAR was seen in macrophages and neutrophils in all cases. We also examined the nonneoplastic mucosa and found that uPAR was more frequently seen in epithelial cells located at the luminal edge of the crypts in cases with Helicobacter pylori infection than in similar epithelial cells in noninfected mucosa (p = 0.033; chi(2) = 4.54). In conclusion, the expression of uPAR in cancer cells in more than half of the gastric cancer cases suggests that their uPAR-positivity do not contribute to explain the different mortality rates between the 2 countries, however, the actual prevalence of uPAR-positive cancer cells in the gastric cancers may still provide prognostic information.

Neutrophil gelatinase-associated lipocalin (NGAL/Lcn2) is upregulated in gastric mucosa infected with Helicobacter pylori.

Helicobacter pylori infection is one of the most significant risk factors for gastric cancer. The infection is established early in life and persists lifelong leading to a sustained chronic inflammation. Iron is essential for most living organisms. Bacteria use several mechanisms to acquire iron from their hosts, including the synthesis of the potent iron chelators known as siderophores. Hosts cells may express the siderophore-binding protein neutrophil gelatinase-associated lipocalin (NGAL/lipocalin-2 (Lcn2)) in response to infection, thus preventing bacterial iron uptake. We have characterized here the pattern of expression of NGAL/Lcn2 in gastric mucosa (45 non-neoplastic and 38 neoplastic tissue samples) and explored the connection between NGAL/Lcn2 expression and H. pylori infection. Immunohistochemical analysis showed high NGAL/Lcn2 expression in normal and gastritis-affected mucosa compared to low expression in intestinal metaplasia, dysplasia, and gastric cancer. In normal and gastritis-affected mucosa (n=36 tissue samples), NGAL/Lcn2 was more frequently seen in epithelial cells located at the neck and base of the glands in H. pylori-positive cases than in similar epithelial cells of noninfected cases (Fisher's exact test, p=0.04). In conclusion, the high expression of NGAL/Lcn2 in normal and gastritis-affected mucosa infected with H. pylori suggests that NGAL/Lcn2 is upregulated locally in response to this bacterial infection. It is discussed whether this may have a causal relation to the development of gastric cancer.

La inflamación y su papel en el desarrollo del cáncer gástrico / Inflammation and its Role in the Development of Gastric Carcinoma

La infección por Helicobacter pylori produce, en algunos pacientes, inflamación crónica en el estómago, gastritis atrófica y cáncer gástrico. Los mecanismos moleculares que conducen de la infección a la inflamación crónica y al cáncer son desconocidos. La magnitud y el proceso de la inflamación dependen del tipo de cepa de H. pylori y de la respuesta del hospedero ante la infección. Esta respuesta inflamatoria está regulada por citoquinas, algunas de las cuales han sido asociadas con cambios en la secreción de ácido en el estómago y con el riesgo de desarrollar cáncer gástrico y varias lesiones gástricas precancerosas. Sin embargo, la relación entre citoquinas y cáncer gástrico no es del todo clara. Esta revisión se enfoca en los procesos inflamatorios asociados con el desarrollo del cáncer gástrico.

Helicobacter pylori infection results, in some patients, in chronic inflammation of the stomach, atrophic gastritis and gastric cancer. The molecular mechanisms that lead from infection to chronic inflammation and gastric cancer are not understood. The degree of inflammation varies and depends on the H. pylori strain and the host response against the infection. The inflammatory response is regulated by cytokines, some of which have been associated with acid gastric secretion changes and with increased risk of stomach cancer and some precancerous lesions. Nevertheless, the relationship between cytokines and gastric cancer is not clear yet. This review focuses on the inflammatory processes associated with the development of gastric malignancies.

Relation of atrophic gastritis with Helicobacter pylori-CagA(+) and interleukin-1 gene polymorphisms.

AIM: To determine the association of Helicobacter pylori (H pylori) CagA(+) infection and pro-inflammatory polymorphisms of the genes interleukin (IL)-1RN and IL-1B with the risk of gastric atrophy and peptic ulcers in a dyspeptic population in Costa Rica, a country with high incidence and mortality of gastric cancer. METHODS: Seven biopsy specimens, a fasting blood sample and a questionnaire concerning nutritional and sociodemographic factors were obtained from 501 consecutive patients who had undergone endoscopy for dyspeptic symptoms. A histopathological diagnosis was made. Pepsinogen concentrations were analyzed by enzyme linked immunosorbent assay (ELISA). Infection with H pylori CagA(+) was determined by serology and polymerase chain reaction (PCR). IL-1B and IL-1RN polymorphisms genotyping was performed by PCR-restriction fragment length polymorphism (PCR-RFLP) and PCR respectively. RESULTS: In this dyspeptic population, 86% were H pylori positive and of these, 67.8% were positive for CagA. Atrophic antral gastritis (AAG) was associated with CagA(+) status [odd ratio (OR) = 4.1; P < 0.000] and fruit consumption (OR = 0.3; P < 0.00). Atrophic body gastritis (ABG) was associated with pepsinogen PGI/PGII < 3.4 (OR = 4.9; P < 0.04) and alcohol consumption (OR = 7.3; P < 0.02). Duodenal ulcer was associated with CagA(+) (OR = 2.9; P < 0.04) and smoking (OR = 2.4; P < 0.04). PGI < 60 microg/L as well as PGI/PGII < 3.4 were associated with CagA(+). CONCLUSION: In a dyspeptic population in Costa Rica, H pylori CagA(+) is not associated with ABG, but it is a risk factor for AAG. The pro-inflammatory cytokine polymorphisms IL-1B + 3945 and IL-1RN are not associated with the atrophic lesions of this dyspeptic population.

Asociación del polimorfismo del codon 72 del gen p53 con el riesgo de cáncer gástrico en una población de alto riesgo de Costa Rica / Association of the p53 codon 72 polymorphism to gastric cancer risk in a hight risk population of Costa Rica

El cáncer gástrico es la segunda causa de muerte por cáncer en el mundo. Varios factores han sido asociados con el riesgo de llegar a desarrollarlo, entre ellos la predisposición genética. El gen p53 presenta un polimorfismo en el codón 72, el cual ha sido asociado con un mayor riesgo de desarrollar varios tipos de cáncer entre ellos el gástrico. El objetivo de este estudio fue determinar la asociación del polimorfismo localizado en el codón 72 del gen p53 con el riesgo de cáncer gástrico y lesiones gástricas leves en una población de alto riesgo de Costa Rica. El análisis del polimorfismo se llevó a cabo mediante PCR-RFLP, en una muestra de 58 pacientes de cáncer gástrico, 99 personas controles y 41 individuos clasificados como grupos I y II de acuerdo con la clasificación histológica japonesa. No se determinó asociación del polimorfismo del codón 72 de p53 con el riesgo de cáncer gástrico, ni de lesiones gástricas leves en la muestra estudiada. Con base en este estudio y otros que han investigado el polimorfismo del codón 72 del gen p53, no está claro el papel que podría estar jugando dicho polimorfismo en el desarrollo de cáncer gástrico. Mutaciones de novo en el gen p53 producidas durante el desarrollo neoplásico de la enfermedad podrían tener un mayor efecto que polimorfismos de línea germinal de este mismo gen. Existen otros genes polimórficos que también se han asociado con el riesgo de desarrollar cáncer gástrico

Gastric cancer is the second most common cancer associated death cause worldwide. Several factors have been associated with higher risk to develop gastric cancer, among them genetic predisposition. The p53 gene has a polymorphism located at codon 72, which has been associated with higher risk of several types of cancer, including gastric cancer. The aim of this study was to determine the association of p53, codon 72 polymorphism, with the risk of gastric cancer and pre-malignant lesions in a high-risk population from Costa Rica. The genotyping was carried out by PCR-RFLP in 58 gastric cancer patients, 99 controls and 41 individuals classified as group I or II, according to the Japanese histological classification. No association was found for p53, codon 72 polymorphism with neither the risk of gastric cancer nor the risk of less severe gastric lesions in the studied population. Based on this study and taking into account other studies carried out with p53, codon 72 polymorphism, the role of this polymorphism in the development of gastric cancer remains unclear. De novo mutations on p53 gene produced during neoplasic development of this disease might play a greater role than germinal polymorphisms of the gene. Other polymorphic genes have been associated with higher risk to develop gastric cancer