Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress. Molecular carcinogenesis Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury, and inflammation, and therefore, contributes to the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE, and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and EAC (OE19) cell lines were exposed to an acid pulse (pH 3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 h in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression. © 2015 Wiley Periodicals, Inc. 10.1002/mc.22406

Expression, modulation, and clinical correlates of the autophagy protein Beclin-1 in esophageal adenocarcinoma. Weh Katherine M,Howell Amy B,Kresty Laura A Molecular carcinogenesis Esophageal adenocarcinoma (EAC) is characterized by rapidly increasing incidence and mortality rates and poor survival. Efficacious preventive and treatment options are urgently needed. An increasing number of pharmacologic agents targeting cancer cell death via autophagy mechanisms are being evaluated in hopes of circumventing apoptotic and therapeutic resistance. We report for the first time, loss of Beclin-1, a key mediator of autophagy, was significantly linked to prognostic factors in EAC. Specifically, Beclin-1 expression loss occurred in 49.0% of EAC patients versus 4.8% of controls. There was a significant inverse correlation between loss of Beclin-1 with histologic grade and tumor stage supporting a tumor suppressive role for Beclin-1. Autophagy modulation linked to cell death was examined in EAC cell lines following treatment with a proanthocyanidin-rich cranberry extract, C-PAC, and the commonly used autophagy inducer, rapamycin. C-PAC induced Beclin-1-independent autophagy in EAC cells characterized by reduced phosphorylation at serine 15 and 93, and significant cell death induction. In contrast, rapamycin-induced autophagy resulted in concomitant, increases in total Beclin-1 levels as well as Beclin-1-phosphorylation in a cell line specific manner, leading to long-term cell survival. Furthermore, autophagic LC3-II was induced by C-PAC following siRNA suppression of Beclin-1 in EAC cells. Together these data support a prognostic role of Beclin-1 in EAC with evidence that Beclin-dependent autophagy induction is agent specific. Future studies are necessary to fully interrogate the role autophagy plays in the progression of normal tissue to EAC and how specific agents targeting autophagic mechanisms can be efficaciously applied for cancer prevention or treatment. © 2015 Wiley Periodicals, Inc. 10.1002/mc.22432

The expression of LC-3 is related to tumor suppression through angiogenesis in esophageal cancer. Sakurai Toshihide,Okumura Hiroshi,Matsumoto Masataka,Uchikado Yasuto,Setoyama Tetsuro,Omoto Itaru,Owaki Tetsuhiro,Maemura Kosei,Ishigami Sumiya,Natsugoe Shoji Medical oncology (Northwood, London, England) Autophagy is important in the development and remodeling of cells. It is required for cellular adaptation to nutrient deprivation and elimination of damaged organelles. Recently, autophagy has been implicated in carcinogenesis and metastasis. We hypothesized that autophagy-related proteins are initiated until nutrition is supplied by angiogenesis. We evaluated the clinicopathological significance of LC3, an autophagic marker, and its relationship to angiogenesis in patients with esophageal squamous cell carcinoma (ESCC). We immunohistochemically investigated the expression of LC3 as well as endoglin (CD105), a microvessel marker, and vascular endothelial growth factor A (VEGF-A) in 142 patients with ESCC. The high, moderate, and low expression rates of LC3 were 40, 31, and 29 %. LC3 expression inversely correlated with depth of invasion, lymph node metastasis, lymphatic invasion, MVD, VEGF-A expression, and poor prognosis. The overall survival rate was better in patients with high LC3 expression compared to patients with low LC3 expression. We demonstrate that low LC3 expression is related to tumor development as facilitated by angiogenesis and that alteration in LC3 expression is closely related to prognosis. Expression of LC3 proteins is a useful marker for determining tumor prognostic behavior in patients with ESCC. 10.1007/s12032-013-0701-x

Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells. Cellular & molecular biology letters Cancer is the second leading cause of death in South Africa. The critical role that microtubules play in cell division makes them an ideal target for the development of chemotherapeutic drugs that prevent the hyperproliferation of cancer cells. The new in silico-designed estradiol analogue 2-ethyl-3-O-sulfamoylestra-1,3,5(10)16-tetraene (ESE-16) was investigated in terms of its in vitro antiproliferative effects on the esophageal carcinoma SNO cell line at a concentration of 0.18 μM and an exposure time of 24 h. Polarization-optical differential interference contrast and triple fluorescent staining (propidium iodide, Hoechst 33342 and acridine orange) revealed a decrease in cell density, metaphase arrest, and the occurrence of apoptotic bodies in the ESE-16-treated cells when compared to relevant controls. Treated cells also showed an increase in the presence of acidic vacuoles and lysosomes, suggesting the occurrence of autophagic processes. Cell death via autophagy was confirmed using the Cyto-ID autophagy detection kit and the aggresome detection assay. Results showed an increase in autophagic vacuole and aggresome formation in ESE-16 treated cells, confirming the induction of cell death via autophagy. Cell cycle progression demonstrated an increase in the sub-G1 fraction (indicative of the presence of apoptosis). In addition, a reduction in mitochondrial membrane potential was also observed, which suggests the involvement of apoptotic cell death induced by ESE-16 via the intrinsic apoptotic pathway. In this study, it was demonstrated that ESE-16 induces cell death via both autophagy and apoptosis in esophageal carcinoma cells. This study paves the way for future investigation into the role of ESE-16 in ex vivo and in vivo studies as a possible anticancer agent. 10.2478/s11658-014-0183-7

Autophagy and Apoptosis Play Opposing Roles in Overall Survival of Esophageal Squamous Cell Carcinoma. Chen Hsin-I,Tsai Hung-Pei,Chen Yi-Ting,Tsao Shu-Chuan,Chai Chee-Yin Pathology oncology research : POR Esophageal cancer is among the most aggressive gastrointestinal tract malignancies, and squamous cell carcinoma is the most common subtype. Although both autophagy and apoptosis involve programmed cell death, autophagy also maintains cell survival by recycling cellular waste. The relationship between autophagy and apoptosis in esophageal squamous cell carcinoma (ESCC) is unclear. Autophagic and apoptotic markers of ESCC were detected by immunohistochemical staining (IHC) in 43 ESCC patients treated during 2007-2011. Chi-square test and Kaplan-Meier method were used to determine how clinicopathological parameters were related to IHC results for LC3B, Beclin-1 and caspase-3 (CASP-3). Correlations among Beclin-1, LC3B, and CASP-3 were analyzed by Spearman rho. The statistical analyses revealed no clinicopathological parameters that significantly correlated with expressions of Beclin-1, LC3B, and CASP-3. However, low CASP-3 expression and high LC3B expression revealed by IHC were predictors of a poor prognosis. Additionally, LC3B expression had a significant negative correlation with CASP-3 expression. Autophagy is antagonistic to apoptosis and predicts poor overall survival in ESCC. 10.1007/s12253-016-0051-z