Search Results (378)

Cancer is a systemic disease rather than a localized pathology and is characterized by widespread effects, including whole-body exhaustion and chronic inflammation. A thorough understanding of cancer pathophysiology requires a systemic approach that accounts for the complex interactions between cancer cells and host tissues. To explore these dynamics, we employed a comprehensive metabolomic analysis of plasma samples from patients with either esophageal or head and neck squamous cell carcinoma (SCC). Plasma samples from 149 patients were metabolically profiled and correlated with clinical data. Among the metabolites identified, lysophosphatidylcholine (LPC) emerged as the sole biomarker strongly correlated with prognosis. A significant reduction in plasma LPC levels was linked to poorer overall survival. Plasma LPC levels demonstrated minimal correlation with patient-specific factors, such as tumor size and general condition, but showed significant association with the response to immune checkpoint inhibitor therapy. Proteomic and cytokine analyses revealed that low plasma LPC levels reflected systemic chronic inflammation, characterized by high levels of inflammatory proteins, the cytokines interleukin-6 and tumor necrosis factor-α, and coagulation-related proteins. These findings indicate that plasma LPC levels may be used as reliable biomarkers for predicting prognosis and evaluating the efficacy of immunotherapy in patients with SCC. Full article

Early prediction of lymph node metastasis (LNM) following neoadjuvant therapy (NAT) is crucial for timely treatment optimization in esophageal squamous cell carcinoma (ESCC). This study developed and validated a computed tomography-based radiomic model for predicting pathologically confirmed LNM status at the time of surgery in ESCC patients after NAT. A total of 469 ESCC patients from Sun Yat-sen University Cancer Center were retrospectively enrolled and randomized into a training cohort (n = 328) and a test cohort (n = 141). Three signatures were constructed: the tumor-habitat-based signature (Habitat_Rad), derived from radiomic features of three tumor subregions identified via K-means clustering; the multiple instance learning-based signature (MIL_Rad), combining features from 2.5D deep learning models; and the clinicoradiological signature (Clinic), developed through multivariate logistic regression. A combined radiomic nomogram integrating these signatures outperformed the individual models, achieving areas under the curve (AUCs) of 0.929 (95% CI, 0.901–0.957) and 0.852 (95% CI, 0.778–0.925) in the training and test cohorts, respectively. The decision curve analysis confirmed a high net clinical benefit, highlighting the nomogram’s potential for accurate LNM prediction after NAT and guiding individualized therapy. Full article

Background and Objectives: The COVID-19 pandemic disrupted cancer care, prompting adaptations to reduce patient exposure while preserving treatment efficacy. This retrospective observational study compared a weekly cisplatin and 5-fluorouracil (5-FU) regimen to the standard monthly regimen for neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma. Materials and Methods: This single-center retrospective study included 91 patients, divided into two cohorts: weekly chemotherapy (n = 30) and standard chemotherapy (n = 61). Treatment assignment was based on hospital policy changes during the pandemic, with weekly outpatient chemotherapy implemented after November 2022 to conserve inpatient resources. All patients received radiotherapy at 50 Gy in 25 fractions. The weekly regimen consisted of cisplatin 20 mg/m² and 5-FU 800 mg/m², administered over 1–2 h weekly, while the standard regimen administered the same doses over four consecutive days on weeks 1 and 5. Primary endpoints were pathologic complete response (pCR), progression-free survival (PFS), and overall survival (OS). Results: The response rates were similar between groups (weekly: 86.7% vs. standard: 90.2%; p = 0.724). The weekly regimen group showed a higher pCR (40.0% vs. 26.2%; p = 0.181) and significantly lower recurrence (26.7% vs. 52.5%; p = 0.020). Mortality was also reduced in the weekly group (6.7% vs. 34.4%; p = 0.004), though the follow-up duration was shorter (10.6 vs. 22.8 months; p < 0.001). Conclusions: In this retrospective observational study, weekly cisplatin and 5-FU demonstrated comparable efficacy to the standard regimen, with potential advantages in reducing recurrence and mortality. This modified approach may be a viable alternative for maintaining oncologic outcomes while minimizing the burden on healthcare systems during pandemic conditions, although prospective validation is needed. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can help to overcome immunotherapy resistance in ESCC, their severe side effects limit clinical application. This study aimed to explore new resistance mechanisms to immunotherapy in ESCC and identify novel molecular targets to overcome immunotherapy resistance. Methods: We employed immunohistochemistry staining to examine the p-FGFR1^Y654 in tumor samples obtained from 103 patients with ESCC, in addition to evaluating CD8+ T cell infiltration. In vitro expression, western blotting, CCK-8, 5-bromo-2′-deoxyuridine incorporation assays, and migration assays were used to confirm the impact of AZD4547 on p-FGFR1^Y654 expression and the proliferation and migration in ESCC cell lines. Through RNA sequencing analysis, databases such as the Cancer Genome Atlas (TCGA) and Gene Set Cancer Analysis (GSCA), and the reconstruction of transgenic mice using the humanized immune system, we validated the correlation between the expression of p-FGFR1^Y654 and CD8+ T cell infiltration. We also explored how p-FGFR1^Y654 recruits myeloid-derived suppressor cells (MDSCs) through the CXCL8–CXCR2 axis to suppress the therapeutic efficacy of immunotherapy in ESCC. Finally, the tumor-suppressive effects of AZD4547 combined with immunotherapy were confirmed in vivo in tumor-bearing mice with a humanized immune system. Results: We found that the inhibition of p-FGFR1^Y654 expression in ESCC can enhance CD8+ T cell infiltration by suppressing the CXCL8-–XCR2 recruitment of MDSCs. AZD4547, combined with immunotherapy, further promotes immunotherapeutic efficacy in ESCC. Conclusions: In conclusion, our study presents a promising model for combination therapy in ESCC immunotherapy. Full article

Objective: Esophageal cancer (EC) is difficult to visually identify, rendering early detection crucial to avert the advancement and decline of the patient’s health. Methodology: This work aimed to acquire spectral information from EC images via Spectrum-Aided Visual Enhancer (SAVE) technology, which improves imaging beyond the limitations of conventional White-Light Imaging (WLI). The hyperspectral data acquired using SAVE were examined utilizing sophisticated deep learning methodologies, incorporating models such as YOLOv8, YOLOv7, YOLOv6, YOLOv5, Scaled YOLOv4, and YOLOv3. The models were assessed to create a reliable detection framework for accurately identifying the stage and location of malignant lesions. Results: The comparative examination of these models demonstrated that the SAVE method regularly surpassed WLI for specificity, sensitivity, and overall diagnostic efficacy. Significantly, SAVE improved precision and F1 scores for the majority of the models, which are essential measures for enhancing patient care and customizing effective medicines. Among the evaluated models, YOLOv8 showed exceptional performance. YOLOv8 demonstrated increased sensitivity to squamous cell carcinomas (SCCs), but YOLOv5 provided reliable outcomes across many situations, underscoring its adaptability. Conclusions: These findings highlight the clinical importance of combining SAVE technology with deep learning models for esophageal cancer screening. The enhanced diagnostic accuracy provided by SAVE, especially when integrated with CAD models, offers potential for improving early detection, precise diagnosis, and tailored treatment approaches in clinically pertinent scenarios. Full article

Background/Objectives: Esophageal squamous cell carcinoma (ESCC) is a common form of esophageal cancer with a poor prognosis and limited treatment options. Epidermal growth factor receptor (EGFR), an overexpressed oncogenic gene in all ESCC patients, is an attractive target for developing therapies against ESCC. There is an extremely urgent need to develop immunotherapy tools targeting EGFR for the treatment of ESCC. Methods: In this study, we developed human Interleukin-21 (hIL-21)-armed, chimeric-antigen-receptor-modified T (CAR-T) cells targeting EGFR as a new therapeutic approach. The CAR contains a variable domain of the llama heavy chain of heavy-chain antibodies (VHHs), also known as nanobodies (Nbs), as a promising substitute for the commonly used single-chain variable fragment (ScFv) for CAR-T development. Results: We show that nanobody-derived, EGFR-targeting CAR-T cells specifically kill EGFR-positive esophageal cancer cells in vitro and in animal models. Human IL-21 expression in CAR-T cells further improved their expansion and antitumor ability and were observed to secrete more interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and Interleukin-2 (IL-2) when co-cultured with ESCC cell lines in vitro. More CD8⁺ CAR-T cells and CD3⁺CD8⁺CD45RO⁺CD62L⁺ central memory T cells were detected in CAR-T cells expressing hIL-21 cells. Notably, hIL-21-expressing CAR-T cells showed superior antitumor activity in vivo in a KYSE-150 xenograft mouse model. Conclusions: Our results show that hIL-21-armed, nanobody-derived, EGFR-specific CAR-T cell therapy is a highly promising option for treating ESCC patients. Full article

(1) Objective: Cold atmospheric plasma (CAP) is a safe and effective alternative to radiotherapy for cancer treatment. Its anticancer effects are attributed to increased intracellular reactive oxygen species (ROS). Glutathione, a key antioxidant derived from glutamine, is critical for cell proliferation. This study investigated whether CAP-induced ROS elevation results from reduced glutamine–glutathione conversion and elucidates the underlying mechanisms. (2) Methods: Using esophageal squamous carcinoma cell models (Ec9706 and Eca109), we analyzed CAP’s effects on key enzymes in glutamine metabolism (Glutaminase 1 and γ-glutamylcysteine ligase) and proliferation-related genes (e.g., Retinoblastoma and Nuclear respiratory factor 2). Transcriptome analysis further explored molecular pathways involved in CAP-mediated anticancer effects. (3) Results: CAP reduced Glutaminase 1 and γ-glutamylcysteine ligase expression, leading to lower intracellular glutathione, higher ROS activity, and enhanced apoptosis. Transcriptome data confirmed CAP’s role in oxidation-reduction reactions and glutamine metabolism. (4) Conclusions: This study provides the first mechanistic insights into CAP’s anticancer effects by targeting glutamine metabolism. While based on in vitro assays, these findings guide the development of novel CAP therapies for currently incurable cancers. Full article

Bardoxolone methyl, also known as CDDO-Me or RTA 402, is a synthetic oleanane triterpenoid that has garnered significant attention as a potent pharmacological activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a master regulator of cellular redox homeostasis, controlling the expression of genes involved in antioxidant defense, detoxification, and mitochondrial function. By inducing Nrf2 and promoting the transcription of downstream antioxidant response element (ARE)-driven genes, bardoxolone methyl enhances cellular resilience to oxidative stress and inflammation. This mechanism is central not only to its cytoprotective effects but also to its emerging role in oncology. A number of studies investigated the effects of bardoxolone methyl in several malignancies including breast cancer, lung cancer, pancreatic ductal adenocarcinoma, prostate cancer, colorectal cancer, oral and esophageal squamous cell carcinoma, ovarian cancer and glioblastoma. Studies in the literature indicate that bardoxolone methyl exhibits anticancer activity through several mechanisms, including the suppression of cell proliferation, induction of cell cycle arrest and apoptosis, inhibition of epithelial–mesenchymal transition (EMT), and impairment of cancer cell stemness. Additionally, bardoxolone methyl modulates mitochondrial function, reduces glycolytic and oxidative phosphorylation capacities, and induces reactive oxygen species (ROS)-mediated stress responses. In this review, we summarize the available literature regarding the studies which investigated the effects of bardoxolone methyl as anticancer agent. Full article

Background: Opportunistic screening is one major screening approach for esophageal squamous cell carcinoma (ESCC). We aimed to develop a score-based risk stratification model to assess the risk of ESCC and precancerous lesions in opportunistic screening and to validate it in an external population. Methods: The study was a secondary analysis of a published esophageal cancer screening trial. The trial was conducted in 39 secondary or tertiary hospitals in China, with 14,597 individuals including 71 high-grade intraepithelial neoplasia (HGIN) and 182 ESCC, enrolled for opportunistic screening. Additionally, questionnaires and endoscopy were performed. The primary outcome was histology-confirmed high-grade esophageal lesions, including HGIN and ESCC. The predictors were selected using univariable and multivariable logistic regression. Model performance was primarily measured with the area under the receiver operating characteristic curve (AUROC). Results: The score-based prediction model contained 8 variables on a 21-point scale. The model demonstrated an AUROC of 0.833 (95% CI, 0.803–0.862) and 0.828 (95% CI, 0.793–0.864) for detecting high-grade lesions in the training and validation cohorts, respectively. Using the cut-off score determined in the training cohort (≥9), the sensitivity reached 70.0% (95% CI, 50.6–85.3%), 81.3% (95% CI, 63.6–92.8%), and 81.1% (95% CI, 64.9–92.0%) in the validation cohort for detecting HGIN, early ESCC, and advanced ESCC, respectively, at a specificity of 76.4% (95%CI, 75.4–77.4%). The score-based model exhibited satisfactory calibration in the calibration plots. The model could result in 75.6% fewer individuals subjected to endoscopy. Conclusions: This score-based model demonstrated superior discrimination for esophageal high-grade lesions. It has the potential to inform referral decisions in an opportunistic screening setting. Full article

Objective: Esophageal carcinoma (EC) is the eighth most prevalent cancer and the sixth leading cause of cancer-related mortality worldwide. Early detection is vital for improving prognosis, particularly for dysplasia and squamous cell carcinoma (SCC). Methods: This study evaluates a hyperspectral imaging conversion method, the Spectrum-Aided Vision Enhancer (SAVE), for its efficacy in enhancing esophageal cancer detection compared to conventional white-light imaging (WLI). Five deep learning models (YOLOv9, YOLOv10, YOLO-NAS, RT-DETR, and Roboflow 3.0) were trained and evaluated on a dataset comprising labeled endoscopic images, including normal, dysplasia, and SCC classes. Results: Across all five evaluated deep learning models, the SAVE consistently outperformed conventional WLI in detecting esophageal cancer lesions. For SCC, the F1 score improved from 84.3% to 90.4% in regard to the YOLOv9 model and from 87.3% to 90.3% in regard to the Roboflow 3.0 model when using the SAVE. Dysplasia detection also improved, with the precision increasing from 72.4% (WLI) to 76.5% (SAVE) in regard to the YOLOv9 model. Roboflow 3.0 achieved the highest F1 score for dysplasia of 64.7%. YOLO-NAS exhibited balanced performance across all lesion types, with the dysplasia precision rising from 75.1% to 79.8%. Roboflow 3.0 also recorded the highest SCC sensitivity of 85.7%. In regard to SCC detection with YOLOv9, the WLI F1 score was 84.3% (95% CI: 71.7–96.9%) compared to 90.4% (95% CI: 80.2–100%) with the SAVE (p = 0.03). For dysplasia detection, the F1 score increased from 60.3% (95% CI: 51.5–69.1%) using WLI to 65.5% (95% CI: 57.0–73.8%) with SAVE (p = 0.04). These findings demonstrate that the SAVE enhances lesion detectability and diagnostic performance across different deep learning models. Conclusions: The amalgamation of the SAVE with deep learning algorithms markedly enhances the detection of esophageal cancer lesions, especially squamous cell carcinoma and dysplasia, in contrast to traditional white-light imaging. This underscores the SAVE’s potential as an essential clinical instrument for the early detection and diagnosis of cancer. Full article

Esophageal squamous cell carcinoma (ESCC), one of the most frequent malignant tumors of the digestive system, is marked by a poor prognosis and high mortality rate. There is a critical need for effective therapeutic strategies with minimal side effects. Isoquercitrin (IQ) is a natural compound with potent antioxidant properties in cancer and cardiovascular diseases. However, its specific effects and mechanisms in ESCC remain largely unexplored. This study aims to investigate the effects of IQ in ESCC cells and elucidate the mechanisms underlying its therapeutic effects. Specifically, its impact on cell proliferation, colony formation, migration, and invasion was assessed using cell viability assay, morphology, transwell, and colony formation assays. The effects on apoptosis were evaluated by flow cytometry, while immunofluorescence (IF) staining and Western blotting were performed to confirm the underlying mechanisms. The in vivo anti-cancer effects of IQ were then evaluated using a xenograft tumor model. Our results demonstrate that IQ inhibits ESCC cell growth and colony formation while promoting its apoptosis by enhancing caspase activation and downregulating Bcl-2 expression. Furthermore, IQ suppresses cell migration by modulating the epithelial–mesenchymal transition-related proteins. Additionally, IQ induces excessive autophagy by promoting reactive oxygen species accumulation and inhibiting the AKT/mTOR signaling pathway. Importantly, IQ effectively reduces tumor growth in vivo, highlighting its potential as a therapeutic agent for ESCC. Full article

Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy with limited therapeutic options. This study investigated the antitumor efficacy and mechanisms of decursin, a natural pyranocoumarin derivative, against ESCC. In vitro analyses demonstrated that decursin selectively inhibited ESCC cell viability (IC50: 14.62 ± 0.61–26.20 ± 2.11 μM across TE-1, KYSE-30, and KYSE-150 cell lines) without affecting normal esophageal epithelial cells (Het-1A). Decursin (10 μM) suppressed colony formation, impaired wound healing (p < 0.001 at 48 h), and reduced Transwell migration/invasion in KYSE-150 cells. Subcutaneous xenograft models revealed significant tumor growth inhibition (p < 0.01) with decursin treatment (10 mg/kg, intraperitoneal), accompanied by no systemic toxicity. Mechanistically, decursin induced G0/G1 cell cycle deceleration (p < 0.01) and apoptosis through ubiquitin–proteasome-mediated degradation of oncoproteins TP63 and SOX2. Time- and dose-dependent protein suppression was reversed by proteasome inhibitor MG-132, but unaffected by lysosomal inhibition. These findings establish decursin as a promising therapeutic agent for ESCC, functioning via proteasomal degradation of key oncogenic drivers, and provide a rationale for decursin’s further development as a targeted monotherapy or chemosensitizer in multimodal regimens. Full article

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy characterized by poor prognosis and a deficiency of effective therapies. Brusatol (Bru), a bioactive component derived from Brucea javanica, exhibits potent anti-tumor activity. However, the pro-apoptotic and anti-metastatic effects of Bru in ESCC remain unclear. ESCC cells were incubated with Bru. The apoptotic status and metastatic capacities of the cells was measured by the Annexin V-FITC/PI, and wound-healing and transwell assays. Potential targets of Bru in ESCC were identified. The mechanisms by which Bru exerts its effects in ESCC cells were explored. Additionally, the typical 4-NQO-induced ESCC mouse model was employed to examine the anti-tumor effect of Bru in vivo. In this study, Bru was found to trigger mitochondria-mediated cell apoptosis (approximately 5.9- and 3.3-fold increases in the level of apoptosis at high concentrations (80 nM) in the KYSE30 and KYSE450 cells) and inhibit metastasis (49% wound closure decreases at high concentrations (80 nM) in both cells, compared to that in the DMSO group) in ESCC cells. In vivo, Bru significantly suppressed ESCC tumorigenesis. Notably, Bru interacts with Akt1, leading to a reduction in the phosphorylation level of Akt1 at Ser473. Consequently, this not only induced dephosphorylation of Bad at the Ser136 residue to promote mitochondrial apoptosis but also inhibited metastasis in ESCC cells. Bru promoted Bad-mediated mitochondrial apoptosis and inhibited the ESCC cell metastasis by targeting Akt1. Our results suggest Bru is a novel Akt1 inhibitor for inhibiting the progression of ESCC. Full article

Background/Objective: The Empty Spiracles Homeobox 2 (EMX2) gene is a homeobox transcription factor that is critical for the development of the central nervous system and genitourinary system during embryogenesis. EMX2 has been shown to regulate cellular differentiation, migration, and proliferation through its involvement in transcriptional control. Dysregulation of EMX2 expression has been implicated in various pathological conditions, including cancer, but the precise molecular mechanisms underlying EMX2 functions in cancer remain incompletely understood. In this study, we focus on the expression profile and the prognostic significance of EMX2 in esophageal squamous cell carcinoma (ESCC). Methods/Results: The expression levels of EMX2 in clinical ESCC samples varied and appeared to be lower than those in adjacent normal tissues. In addition, EMX2 expression was detected in some of the 20 ESCC cell lines but not in others and was correlated with 5-FU sensitivity. EMX2 expression in ESCC cell lines was strongly associated with colony formation capacity in soft agar, and EMX2 knockdown decreased colony formation. Enforced expression of EMX2 decreased the side population (SP) ratio in FACS analysis but increased colony formation in SP fractions. Although it is a preliminary experiment, xenograft in immunodeficient (NOD) scid mice suggested that the forced expression of EMX2 increased tumorigenic capacity in vivo. A Kaplan–Meyer analysis of patients from whom 20 ESCC cell lines or 18 ESCC tissue samples were obtained indicated that EMX2 expression was a poor prognostic marker. Conclusion: EMX2 has a unique function in ESCC stemness and its expression is the stamped marker of poor prognosis in ESCC patients. Full article

The lethality of esophageal squamous cell carcinoma (ESCC), and other epithelial cancers, is primarily due to its aggressive nature and frequent lymphatic metastasis, both of which impact prognosis. In this review, we explore the underlying molecular mechanisms of ESCC lymphatic metastasis, specifically, the functional role of NRF2 and therapeutic strategies. Current data suggest that NRF2 hyperactivation (NRF2^high) may promote lymphatic metastasis of ESCC by affecting the extracellular matrix (ECM), epithelial–mesenchymal transition (EMT), lymphangiogenesis, immune evasion, metabolic programming, and Hippo signaling. We also update the latest developments in NRF2 inhibitors, their mechanisms of action, screening strategies, and approaches for evaluating compound efficacy. Finally, we highlight the utility of animal models for mechanistic studies and therapeutic development. We believe elucidation of the functional role of NRF2 in ESCC lymphatic metastasis and developing proper NRF2 inhibitors will greatly improve the clinical prognosis of ESCC in human patients. Full article