Esophageal Squamous Carcinoma Patients Research Articles

COL8A1 Regulates Esophageal Squamous Carcinoma Proliferation and Invasion Through PI3K/AKT Pathway.

Esophageal squamous carcinoma (ESCC) is a gastrointestinal malignancy with a high mortality, but the tumorigenesis is still unclear, restricting the target therapy development of ESCC. We explored the role of COL8A1 in ESCC development. Tissue microarrays were used to investigate the expression level of COL8A1 in ESCC tissues. The association between COL8A1 and the overall survival of ESCC patients was assessed. The effect of differential COL8A1 expression on tumor growth was investigated by the xenograft model. The regulation of COL8A1 on tumor growth, migration, and invasion was studied by using ESCC cell lines. The signal transduction pathways involved in COL8A1 were bioinformatically profiled and validated. The COL8A1 was significantly expressed in cancerous tissues and was associated with poor prognosis in patients with ESCC. In vivo, the tumor growth obviously declined after inhibition of the COL8A1 expression. The abilities of cell proliferation and invasion were both decreased when the expression of COL8A1 was knockdown in ESCC cell line. Furthermore, we found the inactivation of the PI3K/AKT pathway that was mediated by knockdown of COL8A1 in ESCC cells, which was reversed with COL8A1 overexpression, whereas the cell proliferation and invasion ability were restored. This is the first report that COL8A1 promote ESCC progression, which hopefully will provide a theoretical basis for clinical targeting of ESCC.

A phase 2 study of fruquintinib in combination with S-1 for second-line treatment of esophageal squamous cell carcinoma after first-line immunotherapy failure.

323 Background: Patients with advanced esophageal squamous carcinoma (ESCC) who experience progression after first-line immunotherapy face a challenging treatment landscape. The potential of anti-vascular therapy combined with chemotherapy in the treatment of esophageal cancer is well-established. Mechanistically, anti-angiogenic agents can promote the normalization of tumor vasculature and facilitate the access of chemotherapeutic agents to tumor targets. Considering the compromised physical condition of advanced ESCC patients, there is a preference for more convenient oral medications. Therefore, we conducted this phase II study to assess the clinical efficacy and safety of combining fruquintinib with S-1 in treating advanced ESCC patients following first-line immunotherapy failure. Methods: This open-label, single-arm, phase II study consists of dose-finding and dose-expansion phases, enrolling advanced or metastatic ESCC patients after first-line immunotherapy failure. The dose-finding phase followed a 3+3 design. Patients received fruquintinib (3mg, 4mg, 5mg, d1-d14, q3w, respectively), in combination with S-1 (40mg, 50mg, 60mg, bid, d1-d14, q3w, based on body surface area (BSA)), until unacceptable toxicities, progressive disease, or death. The initial fruquintinib dose was 4 mg d1-d14, q3w, in combination with an appropriate S-1 dose. Additional patients were enrolled in the dose-expansion phase and received the maximum tolerated dose determined in the dose-finding phase. Results: As of August 1, 2023, seven patients were enrolled in the dose-finding phase. One patient withdrew consent during the DLT assessment period. Among the patients administered a 4mg dose of fruquintinib, one out of three achieved a confirmed partial response (PR) after 7 cycles of treatment. Additionally, two out of three patients at the 5mg dose level achieved PR after 2 cycles of treatment, resulting in an overall response rate (ORR) of 50% (3/6). The disease control rate (DCR) was 100% (6/6). The median progression-free survival (PFS) was observed to be 4.93 months (95% CI: 1.93 – 10.73), with overall survival (OS) at 10.73 months (95% CI: 2.1 – 10.73). In terms of safety, no dose-limiting toxicities (DLTs) were reported at 4mg dose level. While DLTs were observed in two out of the three patients at the 5mg dose level. The most common treatment-related adverse events (TRAE) across all grades were fatigue (5/7) and extremity pain (4/7). Grade 3 TRAE were identified in 5 patients, with hypertension (2/7), mucositis (2/7), and fatigue (2/7) being reported. No grade 4 or higher TRAEs were observed. Conclusions: Potential benefits were demonstrated when using fruquintinib in combination with S-1 for the treatment of ESCC patients after immunotherapy failure. The efficacy and safety of fruquintinib and S-1 will be further investigated in this trial later. Clinical trial information: NCT05636150 .

Positive lymph node ratio is an important index to predict long-term survival for advanced esophageal squamous carcinoma patients (II∼III) with R0 resection--a SEER-based analysis

BackgroundEsophageal squamous carcinoma (ESCC) is one of the most malignant cancers in the world due to nodal metastasis. Therefore, a reasonable nodal staging system is extremely important for further treatment strategies. Recently the positive lymph node ratio (PLNR) is an important prognostic factor in various solid tumors MethodIn this study, we investigated the clinical significance of the PLNR in stage II∼III ESCC patients. We collected the pathological characteristics of 272 stage II∼III ESCC patients from the SEER database from 2004–2016. ROC curves were used to calculate the best cutoff value of the PLNR; Pearson's Chi-square (χ2) and Fisher's exact probability tests were used to compare the clinical baseline and characteristics of patients. For continuous variables, Student's t-test and ANOVA were performed to evaluate statistical significance. Clinical outcomes were estimated by using the Kaplan‒Meier method and log-rank test. Furthermore, univariate and multivariate Cox regression models were utilized to analyze independent prognostic factors of ESCC patients. ResultsConsequently, advanced ESCC patients were effectively stratified into two groups by prognosis using a PLNR cutoff value of 0.15 (P value = 0.04). The median survival time of patients with PLNR <0.15 (n = 145) was much higher than that of patients (n = 127) in the PLNR ≥0.15 group (20.0 vs. 13.0 months, P value < 0.0001). Notably, the PLNR significantly predicted the prognosis of ESCC patients with stage N1 (P value 0.01) and stage III (P value < 0.001) disease. The multivariate Cox proportional hazard model showed that T stage (HR 1.33, 95 % CI 0.97–1.82), tumor size >45 mm (HR 1.32, 95 % CI 1.02–1.70), N stage (HR 1.41, 95 % CI 0.98–2.01) and PLNR ≥0.15 (HR 1.35, 95 % CI 0.87–1.74) were independent risk factors for prognostic prediction in ESCC patients. Meanwhile, 117 II∼III ESCC patients from Shaanxi Provincial People's Hospital shown that the overall survival with a PLNR <0.15 (n = 96) was significantly longer than that with a PLNR ≥0.15 (n = 21) . ConclusionsThe PLNR is useful for accurately predicting clinical outcomes and determining postoperative strategies.

Polymerase iota (POLI) confers radioresistance of esophageal squamous cell carcinoma by regulating RAD51 stability and facilitating homologous recombination

Radiotherapy resistance is an important and urgent challenge in the clinical management of esophageal squamous carcinoma (ESCC). However, the factors mediating the ESCC resistance to radiotherapy and its underlying molecular mechanisms are not fully clarified. Our previous studies have demonstrated the critical role of DNA polymerase iota (POLI) in ESCC development and progression, here, we aimed to investigate the involvement of POLI in ESCC radiotherapy resistance and elucidate the underlying molecular mechanism. We found that highly expressed POLI was correlated with shorter overall survival of ESCC patients received radiotherapy. Down-regulation of POLI sensitized ESCC to IR, prolonged γH2AX foci in nuclei and comet tails after IR. HR but not NHEJ repair is inhibited in POLI-deficient ESCC cells. POLI stabilizes RAD51 protein via competitively binding with and blocking the interaction between RAD51 and E3 ligase XIAP and XIAP-mediated ubiquitination. Furthermore, loss of POLI leads to the activation of GAS signaling. Our findings provide novel insight into the role of POLI in the development of radioresistance mediated by stabilizing RAD51 protein in ESCC.

Identification of the relationship between single-cell N6-methyladenosine regulators and the infiltrating immune cells in esophageal carcinoma

BackgroundN6-methyladenosine (m6A) RNA methylation plays a crucial role in important genomic processes in a variety of malignancies. However, the characterization of m6A with infiltrating immune cells in the tumor microenvironment (TME) in esophageal squamous carcinoma (ESCC) remains unknown. MethodsThe single-cell transcriptome data from five ESCC patients in our hospital were analyzed, and TME clusters associated with prognosis and immune checkpoint genes were investigated. Cell isolation and qPCR were conducted to validate the gene characterization in different cells. ResultsAccording to distinct biological processes and marker genes, macrophages, T cells, and B cells clustered into three to four different subgroups. In addition, we demonstrated that m6A RNA methylation regulators were strongly related to the clinical and biological features of ESCC. Analysis of transcriptome data revealed that m6A-mediated TME cell subsets had high predictive value and showed a close relationship with immune checkpoint genes. The validation results from qPCR demonstrated the characteristics of essential genes. CellChat analysis revealed that RNA from TME cells m6A methylation-associated cell subtypes had substantial and diversified interactions with cancer cells. Further investigation revealed that MIF- (CD74+CXCR4) and MIF- (CD74+CD44) ligand-receptor pairings facilitated communication between m6A-associated subtypes of TME cells and cancer cells. ConclusionOverall, our study demonstrated for the first time the function of m6A methylation-mediated intercellular communication in the microenvironment of tumors in controlling tumor development and anti-tumor immune regulation in ESCC.

A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling

Esophageal squamous carcinoma (ESCC) is a common malignant cancer. Although the non-coding roles of circRNAs in the pathogenesis of human tumors have been well studied, whether circRNAs participate in the progression of ESCC by encoding novel proteins remains unclear. In this study, we identified an overexpression circRNA with protein-coding ability in ESCC tissues, called circUBE4B, whose expression level is correlated with tumor size and tumor differentiation level of ESCC patients. Moreover, a higher level of circUBE4B in ESCC patients is correlated with a worse prognosis. Functionally, we found that circUBE4B promoted the proliferation of ESCC cells by encoding a novel cancer-promoting protein, circUBE4B-173aa. Mechanistically, the circUBE4B-173aa protein interacts with MAPK1 and promotes the phosphorylation level of MAPK1 to eventually activate MAPK/ERK signaling pathway. The xenograft model revealed that overexpression of circUBE4B-173aa in ESCC cells significantly promoted the growth of grafts. Our study provides new insights into the mechanism of circRNA in the development of ESCC and circUBE4B-173aa has the potential to serve as a biomarker and a novel therapeutic target for ESCC therapy.

Role of Lower Esophageal Squamous Cell Carcinoma Margin Location on Abdominal Lymph Node Metastasis Risk

Different sites of esophageal cancer are accompanied by different regional lymph node metastasis (LNM) risks. We aimed to investigate the impact of a lower tumor margin on abdominal LNM risk. We enrolled patients who underwent esophagectomy for esophageal squamous carcinoma (ESCC) from 2014 to 2017 in West China Hospital. Overall survival (OS) analysis was performed. We measured the distance between the lower tumor margin and esophagogastric junction (LED) with upper gastrointestinal contrast-enhanced X-ray (UGCXR). Multivariate logistic regression analysis and propensity score matching (PSM) were performed to explore the relationship between LED and the risk of abdominal LNM. Abdominal LNM risk in ESCC was stratified based on the location of the lower tumor margin. A model predicting abdominal LNM risk was constructed and presented with a nomogram. The included patients had an abdominal LNM rate of 48.29%. In multivariate logistic regression analysis, LED was identified as a risk factor for abdominal LNM. Subgroup analysis of middle ESCC showed that patients with an LED less than 10 cm had a significantly higher rate of abdominal LNM than those with an LED greater than 10 cm. The abdominal LNM rate in middle ESCC patients with an LED less than 10 cm was 32.2%, while it was 35.1% in lower ESCC patients whose lower tumor margin did not invade the esophagogastric junction (EGJ), which was comparable after PSM. LED could help surgeons evaluate the risk of abdominal LNM preoperatively and better guide dissection of abdominal lymph nodes according to risk level.

Prognostic nomogram and risk factors for predicting survival in patients with pT2N0M0 esophageal squamous carcinoma

This study analyzed the impact of factors affecting overall survival in patients with pT2N0M0 esophageal squamous carcinoma (ESCC) and developed a nomogram to predict overall survival (OS). We reviewed the clinical data of 413 patients with pathological T2N0M0 ESCC after radical esophagectomy in two hospitals. Data from one institution was used as the training cohort. A nomogram was established using Cox proportional hazard regression for identifying the prognostic factors affecting for OS in ESCC patients. The area under the curve (AUC), calibration curves and decision curve analysis (DCA) were used to evaluate prognostic efficacy, which was validated in an independent validation cohort. In the training cohort (N = 304), the median OS was 69.33 months, and the 3-, 5- and 10-year OS rates were 76.80%, 67.00% and 56.90%, respectively. The median OS of the validation cohort (N = 109) was 73.50 months, and the 3-, 5- and 10-year OS rates were 77.00%, 67.80% and 55.60%, respectively. According to Cox univariate and multivariate analyses, sex, age, tumor length and the number of resected lymph nodes were identified as predictors of OS. We developed nomograms and performed internal and external validation. The time-dependent receiver operating characteristic (ROC) curve and area under the curve (AUC) value, calibration curve and decision curve analysis (DCA) showed good prediction ability of the nomogram. The developed nomogram can effectively predict OS after esophagectomy in patients with pT2N0M0 ESCC.

Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Esophageal Squamous Cell Carcinoma.

Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of 85263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3+ T, B cells, and immunosuppressive cells such as APOC1+ APOE+ macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor-prognostic epithelial-immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74+ CXCR4+ and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1+ APOE+ macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph-node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes.

Comparison of GLIM and PG-SGA for predicting clinical outcomes of patients with esophageal squamous carcinoma resection.

to determine the validity of the Global Leadership Initiative on Malnutrition (GLIM) against the Patient Generated-Subjective Global Assessment (PG-SGA) as a gold standard tool in malnutrition diagnosis, and to assess the impact of malnutrition diagnosed using GLIM and PG-SGA on the clinical outcomes of patients with esophageal squamous carcinoma (ESCC) resection. we prospectively analyzed 182 patients with ESCC who underwent radical esophagectomy. Preoperative malnutrition was diagnosed using GLIM and PG-SGA, and the postoperative clinical outcomes, including postoperative complications, postoperative chest tube indwelling time, length of stay and total hospitalization cost, were recorded. The association between the prevalence of malnutrition defined by the two tools and postoperative clinical outcomes was evaluated. among the 182 ESCC patients, the incidence of malnutrition before surgery was 58.2 % and 48.4 % defined by PG-SGA and GLIM, respectively. GLIM and PG-SGA had good consistency in nutritional assessment of ESCC patients (k = 0.628, p < 0.001). Malnourished patients had higher TNM stages and older ages (all p < 0.05). Patients with malnutrition as assessed by PG-SGA and GLIM had a higher incidence of postoperative complications, a longer indwelling time of chest tube after esophagectomy, longer hospital length of stay, and higher hospitalization costs than patients with good nutrition (p < 0.001). Comparing the predictive efficiency of postoperative complications, the sensitivity of PG-SGA- and GLIM-defined malnutrition were 81.6 % and 79.6 %, the specificity were 50.4 % and 63.2 %, the Youden index were 0.320 and 0.428, and the Kappa value were 0.110 and 0.130, respectively. The areas under ROC curve of PG-SGA- and GLIM-defined malnutrition and postoperative complications were 0.660 and 0.714, respectively. this study indicates the effectiveness of malnutrition diagnosed according to GLIM and PG-SGA in predicting postoperative clinical outcomes among patients with ESCC. Compared with PG-SGA, GLIM criteria can better predict postoperative complications of ESCC. Follow-up analysis of postoperative long-term survival is needed to explore the association between different assessment tools and postoperative long-term clinical outcomes.

Single cell sequencing revealed the mechanism of PD-1 resistance affected by the expression profile of peripheral blood immune cells in ESCC.

Esophageal squamous carcinoma (ESCC) is a highly lethal malignancy with poor prognosis. The effect of transcriptome characteristics of patient immune microenvironment (TME) on the efficacy of immunosuppressive agents is still poorly understood. Here we extracted and isolated immune cells from peripheral blood of patients with PD-1 monoclonal antibody sensitivity and resistance, and conducted deep single-cell RNA sequencing to describe the baseline landscape of the composition, lineage, and functional status of infiltrating immune cells in peripheral blood of patients with esophageal cancer. The transcriptome characteristics of immune cells were comprehensively analyzed, and the dynamic changes of cell percentage, heterogeneity of cell subtypes and interactions between cells were explained. Co-expression and pedigree tracking based on T-cell antigen receptors revealed a significant proportion of highly migratory intertissue-effector T cells. GO and KEGG enrichment pathway Analysis of CD8+ effect-T cells ESCC_S group and ESCC_D1,2 group, found that in the up-regulated enrichment pathway, ESCC_S group enriched more PD-L1 and PD-1 checkpoint pathways expressed in tumors (JUN/NFKBIA/FOS/KRAS/IFNG), which also exist in T cell receptor signaling pathways. MT2A, MT1X and MT1E were differentially expressed in ESCC patients with PD-1 monoclonal antibody resistance, which may be related to the resistance of PD-1 mMAB. This study has an in-depth understanding of the influence of peripheral immune cell infiltration on the sensitivity of monoclonal antibody PD-1 in patients with esophageal cancer, which is helpful to promote the immunotherapy of patients with esophageal cancer.

Urinary protein biomarker panel predicts esophageal squamous carcinoma from control cases and other tumors.

Discovery of noninvasive urinary biomarkers for the early diagnosis of esophageal squamous carcinoma (ESCC). We conducted proteomic analyses of 499 human urine samples obtained from healthy individuals (n = 321) and ESCC (n = 83), bladder cancer (n = 17), breast cancer (n = 12), colorectal cancer (n = 16), lung cancer (n = 33) and thyroid cancer (n = 17) patients from multiple medical centers. Those samples were divided into a discovery set (n = 247) and an independent validation set (n = 157). Among urinary proteins identified in the comprehensive quantitative proteomics analysis, we selected a panel of three urinary biomarkers (ANXA1, S100A8, TMEM256), and established a logistic regression model in the discovery set that can correctly classify the majority of ESCC cases in the validation sets with the area under the curve (AUC) values of 0.825. This urinary biomarker panel not only discriminates ESCC patients from healthy individuals but also differentiates ESCC from other common tumors. Notably, the panel distinguishes stage I ESCC patients from healthy individuals with AUC values of 0.886. On the analysis of stage-specific biomarkers, another combination panel of protein (ANXA1, S100A8, SOD3, TMEM256) demonstrated a good AUC value of 0.792 for stage I ESCC. Urinary biomarker panel represents a promising auxiliary diagnostic tool for ESCC, including early-stage ESCC.

Comprehensive Genome-Scale Analysis of Esophageal Carcinoma With Esophageal Tissue-Resident Micro-Environment Discrepancy.

To figure out the molecular mechanism in the esophageal squamous carcinoma (ESCC) with the discrepancy in the tissue-resident microbiota, we selected clinical features, RNA sequences, and transcriptomes of ESCC patients from The Cancer Genome Atlas (TCGA) website and detailed tissue-resident microbiota information from The Cancer Microbiome Atlas (n = 60) and explored the infiltration condition of particular microbiota in each sample. We classified the tissue-resident micro-environment of ESCC into two clusters (A and B) and built a predictive classifier model. Cluster A has a higher proportion of certain tissue-resident microbiota with comparatively better survival, while Cluster B has a lower proportion of certain tissue-resident microbiota with comparatively worse survival. We showed traits of gene and clinicopathology in the esophageal tissue-resident micro-environment (ETM) phenotypes. By comparing the two clusters’ molecular signatures, we find that the two clusters have obvious differences in gene expression and mutation, which lead to pathway expression discrepancy. Several pathways are closely related to tumorigenesis. Our results may demonstrate a synthesis of the infiltration pattern of the esophageal tissue-resident micro-environment in ESCC. We reveal the mechanism of esophageal tissue-resident microbiota discrepancy in ESCC, which may contribute to therapy progress for patients with ESCC.

NIR-II Navigation with an EGFR-Targeted Probe Improves Imaging Resolution and Sensitivity of Detecting Micrometastases in Esophageal Squamous Cell Carcinoma Xenograft Models.

The survival rate of esophageal squamous carcinoma (ESCC) after surgical resection is estimated to be only 30.3% due to the difficulty in identifying microinfiltration and subtle metastases. In this study, we explored the value of near-infrared fluorescence in the second window (NIR-II) using an epidermal growth factor receptor (EGFR)-targeted probe (cetuximab-IR800) for the intraoperative navigation of ESCC in xenograft mouse models. Immunohistochemical results showed that EGFR was aberrantly expressed in 94.49% (120/127) of ESCC tissues and 90.63% (58/64) of metastatic lymph nodes. Western blot results demonstrated that EGFR protein was highly expressed in ESCC cell lines. Flow cytometry data revealed that cetuximab-IR800 showed a stronger binding specificity in EGFR-positive KYSE-30 cells than in A2780 control cells (P < 0.01). In vivo imaging data showed that the ratio of mean fluorescent intensity (MFI) and tumor to background (TBR) was significantly higher in KYSE-30 subcutaneous tumors with the infusion of cetuximab-IR800 than in those with the infusion of IgG1-IR800 (P < 0.05). Surgical navigation with NIR-II imaging showed that the TBR in orthotopic ESCC was significantly higher than that of NIR in the first window (NIR-I) (2.11 ± 0.46 vs 1.58 ± 0.31, P < 0.05), and NIR-II was more sensitive than NIR-I in detecting subcentimeter metastases (94.87% (37/39) vs 58.97% (23/39), P < 0.001). In conclusion, cetuximab-IR800 with high specificity for ESCC was first used in NIR-II surgical navigation. This probe showed better imaging resolution and higher sensitivity in detecting subtle metastases derived from an orthotopic ESCC model than NIR-I, which indicates that NIR-II has promise in guiding precise surgery for ESCC patients.

Plasma Metabolomics Reveals Diagnostic Biomarkers and Risk Factors for Esophageal Squamous Cell Carcinoma.

Esophageal squamous carcinoma (ESCC) has a high morbidity and mortality rate. Identifying risk metabolites associated with its progression is essential for the early prevention and treatment of ESCC. A total of 373 ESCC, 40 esophageal squamous dysplasia (ESD), and 218 healthy controls (HC) subjects were enrolled in this study. Gas chromatography-mass spectrometry (GC/MS) was used to acquire plasma metabolic profiles. Receiver operating characteristic curve (ROC) and adjusted odds ratio (OR) were calculated to evaluate the potential diagnosis and prediction ability markers. The levels of alpha-tocopherol and cysteine were progressively decreased, while the levels of aminomalonic acid were progressively increased during the various stages (from precancerous lesions to advanced-stage) of exacerbation in ESCC patients. Alpha-tocopherol performed well for the differential diagnosis of HC and ESD/ESCC (AUROC>0.90). OR calculations showed that a high level of aminomalonic acid was not only a risk factor for further development of ESD to ESCC (OR>13.0) but also a risk factor for lymphatic metastasis in ESCC patients (OR>3.0). A low level of alpha-tocopherol was a distinguished independent risk factor of ESCC (OR< 0.5). The panel constructed by glycolic acid, oxalic acid, glyceric acid, malate and alpha-tocopherol performed well in distinguishing between ESD/ESCC from HC in the training and validation set (AUROC>0.95). In conclusion, the oxidative stress function was impaired in ESCC patients, and improving the body’s antioxidant function may help reduce the early occurrence of ESCC.

S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis.

Dysregulated expression of S100A7 is found in several cancers and plays an important role in tumor progression; however, its carcinogenic role in esophageal squamous carcinoma (ESCC) is still poorly understood. Here, we identified that the levels of S100A7 were remarkably upregulated in 341 tumor tissues (P < .001) and 274 serum samples (P < .001) of ESCC patients compared with normal control. It was an independent prognostic factor (P = .026). Furthermore, a new diagnostic model for ESCC based on serum S100A7, SCC, and crfra21‐1 was established with area under curve (AUC) up to 0.863 (95% CI: 0.802‐0.925). Mechanically, we found upregulated S100A7 could promote cell migration and proliferation through intracellular binding to JAB1 and paracrine interaction with RAGE receptors and then activates the downstream signaling pathways. In addition, exocrine S100A7 could promote M2 macrophage infiltration and polarization by up‐regulating M2 macrophage associated proteins, and tumor angiogenesis by enhancing the activation of p‐ErK and p‐FAK pathways. Further animal experiments confirmed the role of S100A7 in promoting M2 macrophage infiltration and angiogenesis in ESCC. In conclusion, these findings highlighted the potential diagnostic and prognostic value of S100A7 in patients with ESCC. Meanwhile, our results reveal that S100A7 promotes tumor progression by activating oncogenic pathways and remodeling tumor microenvironment, which paving the way for the progress of S100A7 as a therapeutic target for cancer treatment.

Integrative genome-scale analysis of immune infiltration in esophageal carcinoma

To explore the molecular mechanism in the esophageal squamous carcinoma (ESCC) environment, we selected datasets of ESCC patients from The Cancer Genome Atlas (TCGA) (n = 78) and explored the infiltration condition of 24 immune cells in each sample. We assorted the microenvironment of ESCC into two Infiltration groups (I and II) and built a random forest classifier model. We showed traits of gene and clinicopathology in the tumor microenvironment (TME) phenotypes systematically. Infiltration I had low infiltration of immune cells and immunomodulators but relatively higher mutation load, while Infiltration II was enriched with cytotoxic T cells and immunosuppressive cells. The upregulation of several immune cytokines like IFN-γ, TNF-β, and PD-L1 was seen in Infiltration II. The infiltration group was an independent predictor of prognosis showed by Multivariable Cox analysis (Infiltration II vs. I, hazard ratio = 2.73, 95% confidence interval = 1.08–6.91, p = 0.03). All the results can be verified in datasets from the Gene Expression Omnibus database (GEO) and our institution (n = 98). Our results demonstrate a synthesis of the infiltration pattern of the immune in ESCC. We reveal the mechanism of TME, which may contribute to the progress of immunotherapy for patients with ESCC.

The high expression of MTH1 and NUDT5 predict a poor survival and are associated with malignancy of esophageal squamous cell carcinoma.

BackgroundMTH1 and NUDT5 effectively degrade nucleotides containing 8-oxoguanine. MTH1 and NUDT5 have been linked to the malignancy of multiple cancers. However, their functions in tumor growth and metastasis in esophageal squamous carcinoma (ESCC) remain obscure. Our present study aims to explore their prognostic value in ESCC and investigate their function in MTH1 or NUDT5-knockout tumor cells.MethodsMTH1 and NUDT5 protein expression in ESCC adjacent normal tissues and tumor tissues was examined by immunohistochemistry staining. Kaplan–Meier curves were used to assess the association between their expression and overall survival (OS) in ESCC patients. Univariate and Multivariate Cox regression analyses were generated to determine the correlation between these protein expression and OS of ESCC patients. Protein expression in ESCC cell lines were measured by Western blotting. To explore the potential effects of the MTH1 and NUDT5 protein in ESCC, cell models with MTH1 or NUDT5 depletion were established. CCK-8, cell cycle, Western blotting, migration and invasion assays were performed.ResultsOur present study demonstrated that the levels of MTH1 and NUDT5 were upregulated in ESCC cell lines and ESCC tissues, the expression of MTH1 and NUDT5 in ESCC tissues was significantly higher than in adjacent non-tumorous, and higher levels of MTH1 and NUDT5 predicted a worse prognosis in patients with ESCC. MTH1 and NUDT5 are novel biomarkers of the progression of ESCC and a poor prognosis. We also found for the first time that the high expression of NUDT5 independently predicted lower OS in patients with ESCC (hazard ratio (HR) 1.751; 95% confidence interval (CI) [1.056–2.903]; p = 0.030). In addition, the depletion of MTH1 and NUDT5 strongly suppressed the proliferation of ESCC cells and significantly delayed the G1 phase of the cell cycle. Furthermore, we found that MTH1 and NUDT5 silencing inhibited epithelial–mesenchymal transition mainly by the MAPK/MEK/ERK dependent pathway, which in turn significantly decreased the cell migration and invasion of ESCC cells. Our results suggested that the overexpression of MTH1 and NUDT5 is probably involved in the tumor development and poor prognosis of ESCC.

Prediction of lymph node metastatic status in superficial esophageal squamous cell carcinoma using an assessment model combining clinical characteristics and pathologic results: A retrospective cohort study.

It is important to identify the risk of lymph node metastasis (LNM) in patients with superficial esophageal squamous carcinoma (SESC) who have received endoscopic resection (ER). We aimed to develop a risk-predicting model for metastasis of SESC to lymph nodes using clinicopathological features and pathological results. Clinical data on 539 consecutive patients who underwent esophagectomy for SESC in our hospital were collected. Their post-surgical pathological results were assessed and analyzed. Multivariate logistic regression was used to identify all independent risk factors associated with LNM that then were incorporated into the prediction model. LNM was identified in 53 of 366 patients and 30 of 173 patients by positive histopathological results in the training and validation cohorts. The risk factors associated with LNM were large tumor size, poor tumor grade, deep invasion, and presence of angiolymphatic invasion. The model achieved good discriminatory ability of 0.80 (95%CI, 0.74-0.86) and 0.81 (95%CI, 0.75-0.86) in predicting LNM in the training and validation cohorts respectively. A LNM-predicting nomogram was formed with an area under curve of 0.80 (95% CI, 0.74-0.86), which had well-fitted calibration curves. A prediction model was constructed to generates 3 categories for estimated LNM risk in SESC patients. It provides a practical way of estimation of LNM risk in SESC patients who had received ER.

The prognostic significance of metabolic syndrome and weight loss in esophageal squamous cell carcinoma

Our study aimed to investigate the association between metabolic syndrome and postoperative survival in patients with esophageal squamous cell carcinoma, and evaluate whether metabolic syndrome can predict the prognosis in esophageal cancer patients. The retrospective study reviewed 519 patients with esophageal squamous cell carcinoma who had received esophagetomy and lymphnode dissections in the Department of Thoracic Surgery, Qilu Hospital of Shandong University between January 2007 and December 2011. All patients were followed up until December 2016. The median follow-up time was 39.59 months (range 0.25–72 months). The 3-year and 5-year survival rate was 51.4% and 37.0%, respectively. Kaplan–Meier survival analysis revealed a significant correlation between OS and obesity (P = 0.000), weight loss (P = 0.000), diabetes (P = 0.001) and dyslipidemia (P = 0.030). Multivariate analysis indicated that advanced TNM staging (P = 0.007, HR: 1.760, 95% CI: 1.167–2.654) and more weight loss (P = 0.000, HR: 1.961, 95% CI: 1.697–2.267) were independent factors for adverse prognosis of esophageal squamous carcinoma patients. In contrast, diabetes was a protective factor in the prognosis of patients with esophageal cancer (P = 0.018, HR: 0.668, 95% CI: 0.478–0.933). Our findings suggest that TNM staging, weight changes and diabetes were independent predictors for the prognosis of esophageal cancer patients.