Endoscopic diagnosis and management of early squamous cell carcinoma of esophagus.
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ABSTRACT:
SUBMITTER: Yip HC
PROVIDER: S-EPMC5538983 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Diagnosis and therapy of esophageal carcinoma is challenging and requires a multidisciplinary approach. The purpose of the updated German guideline "Diagnosis and Treatment of Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus-version 3.1" is to provide practical and evidence-based advice for the management of patients with esophageal cancer. Recommendations were developed by a multidisciplinary expert panel based on an extensive and systematic evaluation of the published medical literature and the application of well-established methodologies (e.g. Oxford evidence grading scheme, grading of recommendations). Accurate diagnostic evaluation of the primary tumor as well as lymph node and distant metastases is required in order to guide patients to a stage-appropriate therapy after the initial diagnosis of esophageal cancer. In high-grade intraepithelial neoplasia or mucosal carcinoma endoscopic resection shall be performed. Whether endoscopic resection is the definitive therapeutic measure depends on the histopathological evaluation of the resection specimen. Esophagectomy should be performed minimally invasive or in combination with open procedures (hybrid technique). Because the prognosis in locally advanced esophageal carcinoma is poor with surgery alone, multimodality therapy is recommended. In locally advanced adenocarcinomas of the esophagus or esophagogastric junction, perioperative chemotherapy or preoperative radiochemotherapy should be administered. In locally advanced squamous cell carcinomas of the esophagus, preoperative radiochemotherapy followed by complete resection or definitive radiochemotherapy without surgery should be performed. In the case of residual tumor in the resection specimen after neoadjuvant radiochemotherapy and R0 resection of squamous cell carcinoma or adenocarcinoma, adjuvant immunotherapy with nivolumab should be given. Systemic palliative treatment options (chemotherapy, chemotherapy plus immunotherapy, immunotherapy alone) in unresectable or metastastic esophageal cancer depend on histology and are stratified according to PD-L1 and/or Her2 expression.
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Project description:Alternative splicing (AS) is an important biological process for regulating the expression of various isoforms from a single gene and thus to promote proteome diversity. In this study, RNA-seq data from 15 pairs of matched esophageal squamous cell carcinoma (ESCC) and normal tissue samples as well as two cell lines were analyzed. AS events with significant differences were identified between ESCC and matched normal tissues, which were re-annotated to find protein coding genes or non-coding RNAs. A total of 45,439 AS events were found. Of these, 6019 (13.25%) significant differentially AS events were identified. Exon skipping (SE) events occupied the largest proportion of abnormal splicing events. Fifteen differential splicing events with the same trends of ΔΨ values in ESCC tissues, as well in the two cell lines were found. Four pathways and 20 biological processes related to pro-metastasis cell junction and migration were significantly enriched for the differentially spliced genes. The upregulated splicing factor SF3B4, which regulates 92 gene splicing events, could be a potential prognostic factor of ESCC. Differentially spliced genes, including HNRNPC, VCL, ZNF207, KIAA1217, TPM1 and CALD1 are shown with a sashimi plot. These results suggest that cell junction- and migration-related biological processes are influenced by AS abnormalities, and aberrant splicing events can be affected by splicing factor expression changes. The involved splicing factor SF3B4 was found to be a survival-related gene in ESCC and is presumed to regulate AS in multiple cancers. In summary, we identified significant differentially expressed AS events which may be related to the development of ESCC.
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Project description:Barrett's esophagus (BE) is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). Risk factors for EAC overlap with those for esophageal squamous cell carcinoma (ESCC), but ESCC is surprisingly rare in BE. We report two cases of ESCC directly surrounded by BE. Both patients had a previous medical history of cancers, i.e., head and neck squamous cell carcinomas, and were using alcohol and smoking tobacco. Using immunohistochemistry for p63, CK5, CK7, and CDX2, it was confirmed that these carcinomas were pure squamous cell carcinomas, and not EACs or esophageal adenosquamous carcinomas arising from BE. Using TP53 mutation and loss of heterozygosity analysis, we established that the ESCCs in BE were not metastases of the previously diagnosed head and neck squamous cell carcinomas but de novo primary ESCCs. This study shows the strength of molecular analysis as an adjunct to the histopathologic diagnosis for distinguishing between metastases of prior cancers and primary cancers. Furthermore, these cases imply that presence of BE is not protective with regards to developing ESCC in the lower one third of the esophagus. We suggest that their ESCCs arose from islets of squamous epithelium in BE.
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Project description:Early diagnosis of oral squamous cell carcinoma (OSCC) is an attractive strategy to increase survival rate of patient. An integrated separation approach of reversed phase liquid chromatography and hydrophilic interaction chromatography combining with time of flight mass spectrometer has been firstly developed for performing global saliva metabonomics analysis for early diagnosis of OSCC. This approach was designed to overcome the limitations of a single chromatographic method due to different polarity of endogenous metabolites. As a result, 14 potential salivary metabolites were identified. Eight biomarkers up-regulated in OSCC patients are compared with control and six down-regulated groups. Receiver operating characteristic analysis was exploited to evaluate the diagnostic power of the candidate biomarkers, and related metabolic pathways have also been studied. Five salivary biomarkers (propionylcholine, N-Acetyl-L-phenylalanine, sphinganine, phytosphingosine, and S-carboxymethyl-L-cysteine) in combination yielded satisfactory accuracy (AUC = 0.997), sensitivity (100%), and specificity (96.7%) in distinguishing early stage of OSCC from the control. In this study, a comprehensive saliva metabonomics analysis for identifying potential biomarkers to early diagnose OSCC is successfully demonstrated, which has the advantages of non-invasive, simple, reliable, and low-cost. These novel metabolic biomarkers have obvious clinical utility that will help to diagnose OSCC at its early stage.
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Project description:Radiotherapy has been widely used for the clinical management of esophageal squamous cell carcinoma. However, radioresistance remains a serious concern that prevents the efficacy of esophageal squamous cell carcinoma (ESCC) radiotherapy. REV7, the structural subunit of eukaryotic DNA polymerase ζ, has multiple functions in bypassing DNA damage and modulating mitotic arrest in human cell lines. However, the expression and molecular function of REV7 in ESCC progression remains unclear. In this study, we first examined the expression of REV7 in clinical ESCC samples, and we found higher expression of REV7 in ESCC tissues compared to matched adjacent or normal tissues. Knockdown of REV7 resulted in decreased colony formation and increased apoptosis in irradiated Eca-109 and TE-1 cells coupled with decreased tumor weight in a xenograft nude mouse model postirradiation. Conversely, overexpression of REV7 resulted in radioresistance in vitro and in vivo. Moreover, silencing of REV7 induced increased reactive oxygen species levels postirradiation. Proteomic analysis of REV7-interacting proteins revealed that REV7 interacted with peroxiredoxin 2 (PRDX2), a well-known antioxidant protein. Existence of REV7-PRDX2 complex and its augmentation postirradiation were further validated by immunoprecipitation and immunofluorescence assays. REV7 knockdown significantly disrupted the presence of nuclear PRDX2 postirradiation, which resulted in oxidative stress. REV7-PRDX2 complex also assembled onto DNA double-strand breaks, whereas REV7 knockdown evidently increased double-strand breaks that were unmerged by PRDX2. Taken together, the present study sheds light on REV7-modulated radiosensitivity through interacting with PRDX2, which provides a novel target for ESCC radiotherapy.
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Project description:Tissue microarray (TMA) technology has been developed to facilitate high-throughput immunohistochemical and in situ hybridization analysis of tissues by inserting small tissue biopsy cores into a single paraffin block. Several studies have revealed novel prognostic biomarkers in esophageal squamous cell carcinoma (ESCC) by means of TMA technology, although this technique has not yet been validated for these tumors. Because representativeness of the donor tissue cores may be a disadvantage compared to full sections, the aim of this study was to assess if TMA technology provides representative immunohistochemical results in ESCC. A TMA was constructed containing triplicate cores of 108 formalin-fixed, paraffin-embedded squamous cell carcinomas of the esophagus. The agreement in the differentiation grade and immunohistochemical staining scores of CK5/6, CK14, E-cadherin, Ki-67, and p53 between TMA cores and a subset of 64 randomly selected donor paraffin blocks was determined using kappa statistics. The concurrence between TMA cores and donor blocks was moderate for Ki-67 (kappa = 0.42) and E-cadherin (kappa = 0.47), substantial for differentiation grade (kappa = 0.65) and CK14 (kappa = 0.71), and almost perfect for p53 (kappa = 0.86) and CK5/6 (kappa = 0.93). TMA technology appears to be a valid method for immunohistochemical analysis of molecular markers in ESCC provided that the staining pattern in the tumor is homogeneous.
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Project description:Endoscopic submucosal dissection (ESD) is a minimally invasive alternative to esophagectomy for early esophageal squamous cell carcinoma (EESCC). The aim of this study was to compare the efficacy and safety of ESD and esophagectomy in EESCC with different depth of invasion. The data of EESCC patients who received ESD or esophagectomy between Jan 2011 to Dec 2018 at our center were retrospectively analyzed. Overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), and procedure-related variables were compared between ESD and esophagectomy patients. 222 EESCC patients underwent ESD, while 184 underwent esophagectomy. No significant differences were found between the two groups in OS (P=0.417), DSS (P=0.423), and RFS (P=0.726). Procedure duration, post-procedure hospital stay, and hospitalization cost were all lower in ESD patients. Oncologic outcomes were similar between the two groups in propensity score-matched analysis. The R0 resection rate was comparable between ESD and esophagectomy groups in the T1a-M1/M2 and M3/SM1 EESCC subgroups; no significant differences were found in OS, DSS and RFS. In the SM2/SM3 EESCC subgroup, although the prognosis of the two treatment groups was similar, the R0 resection rate was significantly lower in ESD patients than in esophagectomy patients. Thus, we concluded ESD could be a first-line treatment for T1a-M1/M2 and M3/SM1 EESCC as oncologic outcome is comparable to that achieved with esophagectomy with minimal invasion, lower cost and lower incidence of serious adverse events. However, in SM2/SM3 EESCC patients, esophagectomy may be preferable.
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Project description:Extracellular matrix, either produced by cancer cells or by cancer-associated fibroblasts, influences angiogenesis, invasion, and metastasis. Chondroitin/dermatan sulfate (CS/DS) proteoglycans, which occur both in the matrix and at the cell surface, play important roles in these processes. The unique feature that distinguishes DS from CS is the presence of iduronic acid (IdoA) in DS. Here, we report that CS/DS is increased five-fold in human biopsies of esophagus squamous cell carcinoma (ESCC), an aggressive tumor with poor prognosis, as compared with normal tissue. The main IdoA-producing enzyme, DS epimerase 1 (DS-epi1), together with the 6-O- and 4-O-sulfotransferases, were highly upregulated in ESCC biopsies. Importantly, CS/DS structure in patient tumors was significantly altered compared with normal tissue, as determined by sensitive mass spectrometry. To further understand the roles of IdoA in tumor development, DS-epi1 expression, and consequently IdoA content, was downregulated in ESCC cells. IdoA-deficient cells exhibited decreased migration and invasion capabilities in vitro, which was associated with reduced cellular binding of hepatocyte growth factor, inhibition of pERK-1/2 signaling, and deregulated actin cytoskeleton dynamics and focal adhesion formation. Our findings show that IdoA in DS influences tumorigenesis by affecting cancer cell behavior. Therefore, downregulation of IdoA by DS-epi1 inhibitors may represent a new anticancer therapy.
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Project description:BackgroundThe goal of our study was to screen tumor grade-related lncRNAs and mRNAs to reveal the underlying molecular mechanism of esophagus squamous cell carcinoma (ESCC).MethodsThe lncRNA and mRNA sequencing data were obtained from The Cancer Genome Atlas (TCGA). Tumor grade correlation analysis of lncRNAs and mRNAs was executed, followed by the functional enrichment analysis of all tumor grade-related mRNAs. The differentially expression mRNAs (DEmRNAs) and differentially expressed lncRNAs (DElncRNAs) were obtained. PPI network and DEmRNA-DElncRNA interaction analysis were constructed. The functional annotation of the DEmRNAs co-expressed with DElncRNAs was performed. The expression levels of the candidate genes were validated using qRT-PCR.ResultsA total of 1864 tumor grade-related mRNAs (846 positively related and 1018 negatively related) and 552 tumor grade-related lncRNAs (331 positively related and 221 negatively related) were obtained. The top 10 significantly grade-related mRNAs and lncRNAs included CA12, FABP4, DECR1, BAIAP2, IL1RAPL2, PPARD, LAD1, TSPAN10, LDOC1, ZNF853, RP11-25G10.2, RP11-557H15.3, RP11-521D12.5, CHKB-AS1, RP11-219B4.3, CH17-335B8.4, RP11-99 J16-A.2, CTB-111H14.1, ADNP-AS1, and JHDM1D-AS1. SFN, IL1RAPL2, and RP11-25G10.2 were overlapped from grade 1, grade 2, and grade 3. PPI network showed that top 10 proteins with higher degrees, including GNAI1, RAP2B, GNAZ, SHH, ADCY1, PRKAR2B, SH3GL1, GNA15, and ARRB1. A DElncRNAs-nearby DEmRNAs network was constructed to obtain hub lncRNAs including ADAMTS9-AS2, RP11-210 M15.2, RP11-13 K12.1, ZBED3-AS1, and RP11-25G10.2. Except for RP11-25G10.2, ADAMTS9-AS1, ZBED3-AS1, SFN, ATP1A2, and GNA15 were consistent with our TCGA analysis.ConclusionsAlterations of DEmRNAs and DElncRNAs may provide key insights into the molecular mechanisms of ESCC.
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