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      LC3B globular structures correlate with survival in esophageal adenocarcinoma

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          Abstract

          Background

          Esophageal adenocarcinoma has the fastest growing incidence of any solid tumor in the Western world. Prognosis remains poor with overall five-year survival rates under 25 %. Only a limited number of patients benefit from chemotherapy and there are no biomarkers that can predict outcome. Previous studies have indicated that induction of autophagy can influence various aspects of tumor cell biology, including chemosensitivity. The objective of this study was to assess whether expression of the autophagy marker (LC3B) correlated with patient outcome.

          Methods

          Esophageal adenocarcinoma tumor tissue from two independent sites, was examined retrospectively. Tumors from 104 neoadjuvant naïve patients and 48 patients post neoadjuvant therapy were assembled into tissue microarrays prior to immunohistochemical analysis. Kaplan-Meier survival curves and log-rank tests were used to assess impact of LC3B expression on survival. Cox regression was used to examine association with clinical risk factors.

          Results

          A distinct globular pattern of LC3B expression was found to be predictive of outcome in both patient groups, irrespective of treatment ( p < 0.001). Multivariate analysis found that this was a strong independent predictor of poor prognosis ( p < 0.001).

          Conclusions

          This distinctive staining pattern of LC3B represents a novel prognostic marker for resectable esophageal adenocarcinoma.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12885-015-1574-5) contains supplementary material, which is available to authorized users.

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          Most cited references34

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          The role of autophagy in cancer development and response to therapy.

          Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy? And how can the autophagic process be manipulated to improve anticancer therapeutics?
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            Autophagy in metazoans: cell survival in the land of plenty.

            Cells require a constant supply of macromolecular precursors and oxidizable substrates to maintain viability. Unicellular eukaryotes lack the ability to regulate nutrient concentrations in their extracellular environment. So when environmental nutrients are depleted, these organisms catabolize existing cytoplasmic components to support ATP production to maintain survival, a process known as autophagy. By contrast, the environment of metazoans normally contains abundant extracellular nutrients, but a cell's ability to take up these nutrients is controlled by growth factor signal transduction. Despite evolving the ability to maintain a constant supply of extracellular nutrients, metazoans have retained a complete set of autophagy genes. The physiological relevance of autophagy in such species is just beginning to be explored.
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              Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance.

              Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of Bcr-Abl, including T315I. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. Disrupting autophagy by chloroquine treatment enhances SAHA-induced superoxide generation, triggers relocalization and marked increases in the lysosomal protease cathepsin D, and reduces the expression of the cathepsin-D substrate thioredoxin. Finally, knockdown of cathepsin D diminishes the potency of this combination, demonstrating its role as a mediator of this therapeutic response. Our data suggest that, when combined with HDAC inhibitors, agents that disrupt autophagy are a promising new strategy to treat imatinib-refractory patients who fail conventional therapy.
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                Author and article information

                Contributors
                353(0)21 4901333 , s.mckenna@ucc.ie
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                12 August 2015
                12 August 2015
                2015
                : 15
                : 582
                Affiliations
                [ ]Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College, Cork, Ireland
                [ ]Department of Pathology, Royal College of Surgeons Ireland (RCSI), Beaumont Hospital, Dublin, Ireland
                [ ]National Liver Institute, Menoufiya University, Shebin El Kom, Egypt
                [ ]Department of Surgery & Trinity Centre for Health Sciences, St James Hospital, Dublin, Ireland
                [ ]Department of Oncology, Cork University Hospital, Cork, Ireland
                Article
                1574
                10.1186/s12885-015-1574-5
                4533787
                26265176
                16df29ea-0e3b-4348-bcc4-5c37076c84f2
                © El-Mashed et al. 2015

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 8 May 2015
                : 27 July 2015
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2015

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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