Gastric adenocarcinoma is the second most lethal cancer worldwide with only a minority of gastric adenocarcinomas diagnosed in a curable and resectable form [1,2]. Helicobacter pylori is considered the most important risk factor for gastric cancer, by promoting a multi-step process of chronic gastritis, atrophy, intestinal metaplasia, dysplasia and, finally, intestinal-type adenocarcinoma [3]. Secondary prevention through diagnosis of premalignant lesions and early gastric cancer, and screening or follow-up of individuals at high risk, would probably be the most immediate strategies for improving survival [4,5]. Endoscopy examination is therefore of paramount importance. However, endoscopic evaluation of gastric mucosa correlates poorly with histological findings [6,7], and it is not surprising that ancillary techniques such as chromoendoscopy have been used for an accurate diagnosis of precancerous lesions and/or invasiveness of cancerous lesions [8 -10]. Even so, for diverse reasons these methods are not very popular among endoscopists, particularly those in Western countries. Diverse descriptions of new methods of electronic chromoendoscopy, namely high resolution with narrow band imaging (NBI), with or without magnification, have been published [11 -24]. Good results have been reported for the imaging of intestinal metaplasia and cancer; however, reliability * The authors contributed equally to this study and should be considered joint first authors. Pimentel-Nunes P et al. NBI in gastric precancerous and cancer lesions … Endoscopy 2012; 44: 236-246Background and study aim: The reliability and external validity of narrow band imaging (NBI) in the stomach have not been described consistently. The aim of the current study was to describe and estimate the accuracy and reliability of a simplified classification system for NBI in the diagnosis of gastric lesions. Methods: Consecutive patients undergoing NBI endoscopy at two reference centers (n = 85, 33 % with dysplasia) were included in two studies. In total, 224 different areas were biopsied and recorded onto video. In the derivation study, previously described NBI features were analyzed in order to develop a simplified classification. In the validation study the accuracy and reliability of this classification were estimated among three groups of endoscopists with different levels of expertise in NBI. Results: The reliability/accuracy results from the derivation study allowed the creation of a simplified NBI classification. In the validation study, "regular vessels with circular mucosa" (pattern A) was associated with normal histology (accuracy 83 %; 95 % confidence interval [CI] 75 % -90 %);
Invasive bladder tumours express the cell-surface Sialyl-Tn (STn) antigen, which stems from a premature stop in protein O-glycosylation. The STn antigen favours invasion, immune escape, and possibly chemotherapy resistance, making it attractive for target therapeutics. However, the events leading to such deregulation in protein glycosylation are mostly unknown. Since hypoxia is a salient feature of advanced stage tumours, we searched into how it influences bladder cancer cells glycophenotype, with emphasis on STn expression. Therefore, three bladder cancer cell lines with distinct genetic and molecular backgrounds (T24, 5637 and HT1376) were submitted to hypoxia. To disclose HIF-1α-mediated events, experiments were also conducted in the presence of Deferoxamine Mesilate (Dfx), an inhibitor of HIF-1α proteasomal degradation. In both conditions all cell lines overexpressed HIF-1α and its transcriptionally-regulated protein CA-IX. This was accompanied by increased lactate biosynthesis, denoting a shift toward anaerobic metabolism. Concomitantly, T24 and 5637 cells acquired a more motile phenotype, consistent with their more mesenchymal characteristics. Moreover, hypoxia promoted STn antigen overexpression in all cell lines and enhanced the migration and invasion of those presenting more mesenchymal characteristics, in an HIF-1α-dependent manner. These effects were reversed by reoxygenation, demonstrating that oxygen affects O-glycan extension. Glycoproteomics studies highlighted that STn was mainly present in integrins and cadherins, suggesting a possible role for this glycan in adhesion, cell motility and invasion. The association between HIF-1α and STn overexpressions and tumour invasion was further confirmed in bladder cancer patient samples. In conclusion, STn overexpression may, in part, result from a HIF-1α mediated cell-survival strategy to adapt to the hypoxic challenge, favouring cell invasion. In addition, targeting STn-expressing glycoproteins may offer potential to treat tumour hypoxic niches harbouring more malignant cells.
Background: Gastric cancer (GC) is a major health burden worldwide, with half of patients developing metastases within 5 years after treatment, urging novel biomarkers for diagnosis and efficient therapeutic targeting. Sialyl-Lewis A (SLeA), a terminal glycoepitope of glycoproteins and glycolipids, offers tremendous potential towards this objective. It is rarely expressed in healthy tissues and blood cells, while it is present in highly metastatic cell lines and metastases. SLeA is also involved in E-selectin mediated metastasis, making it an ideal target to control disease dissemination. Methods and Results: To improve cancer specificity, we have explored the SLeA-glycoproteome of six GC cell models, with emphasis on glycoproteins showing affinity for E-selectin. A novel bioinformatics-assisted algorithm identified nucleolin (NCL), a nuclear protein, as a potential targetable biomarker potentially involved in metastasis. Several immunoassays, including Western blot and in situ proximity ligation reinforced the existence of cell surface NCL-SLeA glycoforms in GC. The NCL-SLeA glycophenotype was associated with decreased survival and was not reflected in relevant healthy tissues. Conclusions: NCL-SLeA is a biomarker of poor prognosis in GC holding potential for precise cancer targeting. This is the first report describing SLeA in preferentially nuclear protein, setting a new paradigm for cancer biomarkers discovery and targeted therapies.
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