Guodong Deng

The relationship between vasculogenic mimicry and epithelial-mesenchymal transitions

Vasculogenic mimicry (VM) is a vascular‐like structure which can mimic the embryonic vascular network pattern to nourish the tumour tissue. As a unique perfusion way, VM is correlated with tumour progression, invasion, metastasis and lower 5‐year survival rate. Notably, epithelial‐mesenchymal transition (EMT) regulators and EMT‐related transcription factors are highly up‐regulated in VM‐forming tumour cells, which demonstrated that EMT may play a crucial role in VM formation. Therefore, the up‐regulation of EMT‐associated adhesion molecules and other factors can also make a contribution in VM‐forming process. Depending on these discoveries, VM and EMT can be utilized as therapeutic target strategies for anticancer therapy. The purpose of this article is to explore the advance research in the relationship of EMT and VM and their corresponding mechanisms in tumorigenesis effect.

The prognostic value of cytotoxic T-lymphocyte antigen 4 in cancers: a systematic review and meta-analysis

The outcomes of studies analyzing the prognostic role of CTLA-4 in cancers are controversial. Therefore, the aim of our meta-analysis was to clarify the correlation between CTLA-4 expression and OS in different cancer cases. Relevant literature was searched using PubMed, EMBASE, Web of Science, and the Cochrane Library. The clinicopathological features, hazard ratio (HR) and 95% confidence intervals (CI) were collected from these studies and were analyzed using Stata version 12.0 software. The pooled HR values showed no significant correlation between CTLA-4 expression levels and OS in relation to tumors (HR: 1.24, 95% CI: 0.98–1.56, I2 = 71.7%, P = 0.000). Further subgroup analyses were conducted and categorized by experimental methods, CTLA-4 sources and cancer types. The survey showed a significant correlation (HR: 1.47, 95% CI: 1.14–1.89) between high expression of CTLA-4 and OS in the SNP subgroup, and subgroups analyzing by PCR (HR: 1.50, 95% CI: 1.20–1.86) and flow cytometry (HR: 2.76, 95% CI: 1.49–5.14). In addition, our analysis observed significant differences between patients and controls in inCTLA-4+CD4+ lymphocytes, surCTLA-4+CD4+ lymphocytes, inCTLA-4+CD8+ lymphocytes, and surCTLA-4+CD8+ lymphocytes. Knowledge of the effects of CTLA-4 could potentially be used to effectively guide appropriate prognosis and therapeutic strategies in cancer patients.

Pulmonary toxicity generated from radiotherapeutic treatment of thoracic malignancies (Review)

Radiation-induced lung injury (RILI) remains a major obstacle for thoracic radiotherapy for the treatment of lung cancer, esophageal cancer and lymphoma. It is the principal dose-limiting complication, and can markedly impair the therapeutic ratio as well as a patients quality of life. The current review presents the relevant concepts associated with RILI, including the pathogenic mechanisms and the potential treatment strategies, so as to achieve a general understanding of this issue. RILI comprises an acute radiation pneumonitis phase and subsequent late lung fibrosis. The established assessment criteria are clinical manifestations, imaging changes and the necessity for medical assistance. Risk factors are also considered in order to optimize treatment planning. Due to the underlying molecular mechanisms of RILI, the present review also discusses several targeted pharmacological approaches for its treatment, as well as corticosteroid therapy.

Soluble cytotoxic T-lymphocyte antigen 4: a favorable predictor in malignant tumors after therapy

Purpose Soluble cytotoxic T-lymphocyte antigen 4 (sCTLA-4), one of the isoforms of CTLA-4, was discovered to be critical in downregulating the negative signal of CTLA-4 in T-cell responses. Contrary to the classical immunosuppressive effect of CTLA-4, its immunoregulatory function might be complicated. However, the clinical significance of sCTLA-4 to immune regulation and the variation in cancer therapy have not been elucidated. We postulated that the level of sCTLA-4 might affect the outcome of cancer prognosis. Patients and methods Serum concentrations of sCTLA-4 before and after therapy in 141 locally advanced and advanced cancer patients were measured and survival analyses was performed. Hazard ratio and 95% confidence interval for overall survival (OS) were calculated. Cutoffs were determined by median across the sCTLA-4 level of entire patients. Results High expression of sCTLA-4 after therapy indicated significant longer OS and progression-free survival (PFS) (all P<0.01). Among all subgroups, sCTLA-4 levels after therapies were found to be significantly higher than that of 1 day before, which was also negatively correlated with tumor node metastasis stage and lymph node metastasis (all P<0.05). Multivariate analysis revealed that sCTLA-4 level was a strong independent prognostic factor for OS and PFS (all P<0.05). Conclusion Our data demonstrated the favorable prognostic significance of sCTLA-4 and may lead to the development of new immunotherapy options for cancer patients.

The effect of induction chemotherapy in patients with locally advanced nonsmall cell lung cancer who received chemoradiotherapy: A systematic review and meta-analysis

Background: The efficacy and toxicity of induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced nonsmall cell lung cancer (NSCLC) is unclear, we performed a systematic review and meta-analysis of published papers to quantitatively evaluate the potential benefit of induction chemotherapy. Methods: Eligible studies of induction chemotherapy and chemoradiotherapy were retrieved through extensive searches of the PubMed, Science Direct, Embase, and Cochrane library databases from 1994 to 2015. We excluded studies that using non-English. Our primary endpoint was overall survival (OS), secondary end point was toxicity. Results: Two studies of induction chemotherapy followed by CCRT versus CCRT alone and 5 studies of induction chemotherapy followed by CCRT versus CCRT followed by consolidation chemotherapy published in the same period were selected and analyzed. Our results showed that there was significant benefit of induction chemotherapy plus CCRT compared to CCRT alone on 5-year OS without 1, 2, 3, and 4 years OS. Our analysis also indicated that induction chemotherapy was as effect as consolidation chemotherapy for patients who received CCRT on overall response and OS. Treatment-related toxicity was similar between the 2 group; however, leucopenia was significant decreased in patients treated by induction chemotherapy (odds ratio [OR] = 0.43; 95% confidence interval [CI], 0.30–0.62; P < 0.00001). Conclusion: Five year OS could be improved when induction chemotherapy was added into CCRT for patients of NSCLC. Except low rate of leucopenia, induction chemotherapy was no difference compared to consolidation chemotherapy in patients with NSCLC treated by CCRT.

Gene silencing of galectin-3 changes the biological behavior of Eca109 human esophageal cancer cells.

Galectin-3 is a multifunctional β-galactoside-binding lectin that is involved in multiple biological functions which are upregulated in malignancies, including cell growth, adhesion, proliferation, progression and metastasis, as well as apoptosis. A previous study has confirmed the roles of galecin-3 overexpression in the biological behavior of Eca109 human esophageal cancer (EC) cells. In the present study, small interfering (si)RNA-mediated galectin-3 silencing was performed to analyze the effects of decreased galectin-3 expression on the biological behavior of EC cells. Western blot and quantitative polymerase chain reaction analyses were utilized to confirm galectin-3 knockdown at the protein and mRNA level (P<0.05 vs. siRNA-control and untransfected groups). Cell proliferation was assessed using the Cell Counting Kit-8 assay. At 72 and 96 h after transfection, the proliferation of Eca109 cells in the siRNA-Gal-3 group was decreased compared with that in the siRNA-Control and untransfected groups (P<0.001 and P=0.004, respectively). Furthermore, Transwell assays demonstrated that inhibition of galecin-3 significantly reduced the migration and invasion of Eca109 cells compared with that in the other groups (P<0.05). Finally, apoptosis of Eca109 cells was detected using Annexin V/7-amino-actinomycin double-staining and flow cytometric analysis. Galectin-3 knockdown significantly enhanced the apoptotic rate of Eca109 cells compared with that in the siRNA-control and untreated groups (P=0.031 and P=0.047, respectively). In conclusion, following successful knockdown of galecin-3 expression in Eca109 cells, the cell proliferation, migration and invasion were reduced, while the apoptosis was enhanced, which indicates that galectin silencing may represent a therapeutic strategy for EC.

Elevated serum granulocyte-macrophage colony-stimulating factor levels during radiotherapy predict favorable outcomes in lung and esophageal cancer

The combination of exogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) with radiotherapy (RT) has been demonstrated to strengthen the antitumor immune response. We hypothesized that the variation of GM-CSF during RT was correlated with cancer prognosis. We measured serum levels of GM-CSF and interferon-γ (IFN-γ) before and during RT in 126 unresectable lung and esophageal cancer patients and performed survival analyses. Upregulated GM-CSF levels during RT correlated with longer overall survival (OS) and progression-free survival (PFS). On the other hand, no difference in OS or PFS was seen at different IFN-γ levels. However, the “integrated factor”, computed as the combination of high pre-RT IFN-γ levels and upregulated GM-CSF, correlated with prolonged OS and PFS. Multivariate analyses revealed that GM-CSF levels and the integrated factor were both stronger independent prognostic factors than disease stage. These data demonstrate that GM-CSF levels during RT can be used as a prognostic biomarker for lung and esophageal cancer.

Vasculogenic mimicry is associated with increased tumor-infiltrating neutrophil and poor outcome in esophageal squamous cell carcinoma

Purpose Vasculogenic mimicry (VM) is known to be a mechanism to nourish the tumor, but little is known about its prognostic significance in esophageal squamous cell carcinoma (ESCC). We characterized the predictive relevance of VM expression and tumor-infiltrating neutrophil (TIN) density in patients with resectable ESCC. Methods We retrospectively collected clinicopathologic characteristics of 117 esophageal cancer (EC) patients undergoing complete resection and without preoperative therapy. Immunohistochemistry was used to detect the expression of E-cadherin and CD66b. CD34/periodic acid-schiff (PAS) double staining was used to detect the expression of VM. Results VM expression was observed in 56 (47.9%) patients. VM was negatively correlated with E-cadherin (correlation coefficient =−0.364, P<0.001) and was positively correlated with infiltration of CD66b neutrophil (correlation coefficient =0.421, P<0.001). VM and CD66b+ neutrophil infiltration are important markers for poor overall survival and disease-free survival. Multivariate analysis showed that VM, CD66b+ neutrophil infiltration, pathologic tumor node metastasis (TNM) (pTNM) stage, and tumor differentiation are significant independent prognostic predictors in ECs (P=0.001, 0.025, 0.001, 0.011, respectively). VM expression is identified in ~47.9% of ESCC, and it is associated with poor outcome and increased TIN. Conclusion TIN is an important factor for VM formation. Therefore, studies of invasive ability of EC in patients with VM could supply significant information for therapeutic strategy.

Effect of galectin-3 on vasculogenic mimicry in esophageal cancer cells

Galectin-3 is a multifunctional β-galactoside binding lectin associated with tumor progression. Previous studies confirmed the roles of galecin-3 overexpression and silencing in the biological behavior of Eca109 human esophageal cancer (EC) cells; galectin-3 may serve a critical role in the vasculogenic mimicry (VM) of tumors. Therefore, the present study examined the effects of galectin-3 knockdown using lentivirus vectors on VM in EC. Eca109 and EC9706 EC cells were transfected with a lentiviral vector to inhibit galectin-3 expression, or a control vector. VM formation in vitro was evaluated via 3D culture. Western blotting was used to detect the expression level of galectin-3 following galectin-3 silencing and the expression levels of VE-cadherin, ephrin type-A receptor 2 precursor (EphA2) and matrix metalloproteinase 2 (MMP-2). According to the results of western blot analysis, the Eca109/galectin-3 and EC9706/galectin-3 cells exhibited effective galectin-3 silencing (P<0.05). Eca109 and EC9706 cells formed typical tubular networks; the number of tubular networks markedly decreased subsequent to galectin-3 knockdown. The expression levels of MMP-2 and EphA2 proteins in Eca109/galectin-3 and EC9706/galectin-3 cells were lower compared with those in Eca109, EC9706, and control vector-transfected Eca109 and EC9706 cells (P<0.05); however, there was no significant difference in the expression of VE-cadherin proteins. These results indicated that galectin-3 may modulate VM in EC by regulating the EphA2 expression level, which affects VM formation via MMP-2.

Novel role of granulocyte-macrophage colony-stimulating factor: antitumor effects through inhibition of epithelial-to-mesenchymal transition in esophageal cancer

Purpose Recent studies demonstrate the possible antitumor effects of granulocyte-macrophage colony-stimulating factor (GM-CSF); however, the exact mechanism is still unclear. The aim of our study was to analyze the effects of GM-CSF on multiple biological functions of human esophageal cancer (EC) cell lines and to explore the potential mechanism of its antitumor effects. Materials and methods Eca109/9706 human EC cells were examined. Cell proliferation, apoptosis, and migration were analyzed using cell proliferation assay, flow cytometry, and transwell assay, respectively. The expression of signaling molecules were examined by reverse transcription polymerase chain reaction and Western blot. Results Our results provide experimental evidence that GM-CSF inhibits growth and migration, as well as induction of apoptosis in EC cells. In addition, EC cells stimulated with GM-CSF were more likely to have suppressed epithelial-to-mesenchymal transition (EMT), accompanied by increased E-cadherin and decreased vimentin expression. Conclusion Our data demonstrate that GM-CSF inhibits cancer cell proliferation and migration, as well as induction of apoptosis. Moreover, our findings indicate that GM-CSF may regulate EMT through JAK2-PRMT5 signaling, and thereby exhibit its antitumor effects on EC cells.