Xinshuang Yu

Advanced research on vasculogenic mimicry in cancer

Vasculogenic mimicry (VM) is a brand‐new tumour vascular paradigm independent of angiogenesis that describes the specific capacity of aggressive cancer cells to form vessel‐like networks that provide adequate blood supply for tumour growth. A variety of molecule mechanisms and signal pathways participate in VM induction. Additionally, cancer stem cell and epithelial‐mesenchymal transitions are also shown to be implicated in VM formation. As a unique perfusion way, VM is associated with tumour invasion, metastasis and poor cancer patient prognosis. Due to VMs important effects on tumour progression, more VM‐related strategies are being utilized for anticancer treatment. Here, with regard to the above aspects, we make a review of advanced research on VM in cancer.

Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway

Objective This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. Results The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h. Compared with the blank group, the tunicamycin, BEZ235 and tunicamycin + BEZ235 groups exhibited decreased expressions of p-PI3K, p-AKT and p-mTOR, and increased expressions of autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis proteins (Bax and procaspase-3), and the most obvious changes were observed in the tunicamycin + BEZ235 group. Materials and Methods CCK-8 assay was applied to select the best cell line from five SCLC cell lines (NCI-H446, H69, H526, H146 and H209). Finally, NCI-H446 and H69 cells were selected for further experiments. NCI-H446/CDDP and H69/CDDP were selected and divided into the blank group, tunicamycin (an ESR inducer) group, BEZ235 (inhibitors of PI3K/AKT/mTOR pathway) group and tunicamycin + BEZ235 group. Cell apoptosis was detected by flow cytometry. Autophagy was observed by fluorescence microscopy and flow cytometry. Western blotting was used to detect the expressions of ERS-related proteins, autophagy-related proteins, apoptosis-related proteins and PI3K/AKT/mTOR pathway-related proteins. Conclusions Our findings provide evidence that the activation of ERS could promote autophagy and apoptosis and reverse chemoresistance of human SCLC cells by inhibiting the PI3K/AKT/mTOR pathway.

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.

Decreased Tumor Suppressor Candidate 3 Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma.

TUSC3 was recently identified as a potential tumor suppressor gene in a variety of human malignancies. However, no data are currently available regarding the expressions of TUSC3 in esophageal cancer (ESCC).The purposes of this study was to investigated the expressions of TUSC3 in ESCC tissues and assess the relationship between TUSC3 levels and clinico-pathological characteristics of ESCC patients. TUSC3 protein expressions were evaluated by immunohistochemistry (IHC) on tissue microarray slides in esophageal cancer, which included 95 esophageal squamous carcinoma specimens (ESCC), and 75 normal esophageal mucosa (NEM). We found that TUSC3 in ESCC was significant lower than that in NEM (P=0.000). According to multi-clinical classifications, TUSC3 level varied significantly with TNM stage, T stage, and N stage (p<0.001, p=0.0368, p<0.0001, respectively). Univariate analysis showed that gender, TNM stage, T stage, N stage, TUSC3 expression were prognostic factors for survival. Multivariate analysis showed that in our study, only TUSC3 expression was independent prognostic factors for ESCC. Our results indicated for the first time, a combined analysis of TUSC3 expressions as well as the clinical variables will help predict the prognosis of ESCC patients. Further large-sample validation and functional analysis should be performed to evaluate its potential prognostic and therapeutic values for ESCC patients.

Effect of galectin-3 on the behavior of Eca‑109 human esophageal cancer cells.

Galectin-3, a β-galactoside-binding lectin, is a cell adhesion molecule involved in the regulation of tumor progression. However, the importance of galectin-3 in Eca-109 human esophageal cancer cells has not yet been elucidated. In the present study, a lentiviral vector was designed for overexpression of galectin-3 in Eca-109 cells following plasmid-mediated transfection (Eca-109/Gal-3 cells). A negative lentiviral vector was introduced into Eca-109 cells as a control (Eca-109/Neo cells). Western blot and reverse transcription-polymerase chain reaction analyses were used to measure the expression levels of galectin-3 protein and mRNA. The proliferation of Eca-109 cells was measured by a cell counting kit-8 assay. Eca-109 cell apoptosis was determined by Annexin V/7-amino-actinomycin double-staining. The migration and invasion capacity of Eca-109 cells was determined by a Transwell assay. A total of >98% Eca-109 cells were transfected with the lentiviral vector harboring galectin-3, and galectin-3 expression was detected in Eca-109 cells, Eca-109/Gal-3 cells and Eca-109/Neo cells. Compared with non-transfected and negative control Eca-109 cells, proliferation was increased significantly in the Eca-109/Gal-3 cells (P<0.05). Galectin-3 also significantly reduced Eca-109 cell apoptosis, compared with the two control groups (P=0.007 and P=0.04, respectively). Transwell migration and invasion assays revealed that significantly greater numbers of Eca-109/Gal-3 cells crossed the artificial basement membrane (55.4±3.9) compared with either the non-transfected or negative control Eca-109 cells (30.6±1.5 and 29±2.6 respectively, P<0.05). In conclusion, galectin-3 expression was significantly increased in transfected Eca-109 esophageal cancer cells, resulting in enhanced proliferation, migration and invasion, as well as reduced apoptosis. These data indicate that galectin-3 may be a potential molecular target in the treatment of esophageal cancer.

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.

TUSC3: a novel tumour suppressor gene and its functional implications

The tumour suppressor candidate 3 (TUSC3) gene is located on chromosome region 8p22 and encodes the 34 kD TUSC3 protein, which is a subunit of the oligosaccharyl transferase responsible for the N‐glycosylation of nascent proteins. Known to be related to autosomal recessive mental retardation for several years, TUSC3 has only recently been identified as a potential tumour suppressor gene. Based on the structure and function of TUSC3, specific mechanisms in various diseases have been investigated. Several studies have demonstrated that TUSC3 is an Mg2+‐transporter involved in magnesium transport and homeostasis, which is important for learning and memory, embryonic development and testis maturation. Moreover, dysfunction or deletion of TUSC3 exerts its oncological effects as a modulator by inhibiting glycosylation efficiency and consequently inducing endoplasmic reticulum stress and malignant cell transformation. In this study, we summarize the advances in the studies of TUSC3 and comment on the potential roles of TUSC3 in diagnosis and treatment of TUSC3‐related diseases, especially cancer.

Tumor suppressor candidate 3 as a novel predictor for lymph node metastasis in lung cancer patients

Tumor suppressor candidate 3 (TUSC3) was recently identified as a potential tumor suppressor gene in several cancer types. However, no data are currently available regarding the expression of TUSC3 in lung cancer. The present study investigated the expression of TUSC3 in patients with lung cancer and determined its association with the clinicopathological parameters of the disease. Cytoplasmic TUSC3 expression was evaluated by immunohistochemistry on tissue microarray slides, which included 35 small cell lung cancer (SCLC) specimens, 80 squamous cell lung cancer specimens (SCC), 80 adenocarcinoma lung cancer (ADC) specimens and 37 normal lung tissue specimens. Analysis showed significantly reduced TUSC3 expression in the SCLC patients, but not in the ADC and SCC patients, as compared with the normal controls. Additionally, TUSC3 expression in the patients with a degree of differentiation of 1–2 (well-moderately differentiated) was significantly higher than that in patients with a differentiation degree of 3–4 (poorly differentiated-undifferentiated). Further analysis showed that TUSC3 expression levels were negatively correlated with the degree of differentiation in the ADC and SCC patients. Notably, a marked decrease in TUSC3 expression was identified in the patients who were lymph node metastasis-positive (LNM+) compared with patients who were LNM−. Further analysis showed that significant differences in TUSC3 expression were identified among the different N stages (LNM status) in the SCLC, ADC and SCC patients. Correlation analysis also identified a negative correlation between TUSC3 expression and LNM in all three pathological types of lung cancer tested. Overall, these results indicated that a reduction in TUSC3 may be associated with a poorly-differentiated grade of lung cancer. Importantly, TUSC3 expression may be a useful predictor of LNM in lung cancer patients. A combined analysis of TUSC3 expression and the clinical variables will aid in predicting the incidence of LNM.

Male breast metastases from nasopharyngeal carcinoma: A case report and literature review

Nasopharyngeal carcinoma (NPC) is known for its high rate of regional lymph node and distant metastasis. However, NPC rarely metastasizes to the breast and, to the best of our knowledge, only four well-documented cases of breast metastasis have previously been reported in the literature, all of which are female. A 49-year-old male was diagnosed with NPC and developed a right breast mass five months later. Breast fine needle aspiration confirmed an abundance of metastatic squamous cells within the thickened tissue. The current study presents the first male case of breast metastases from NPC to broaden the clinical database.

Tumor suppressor candidate 3: A novel grading tool and predictor of clinical malignancy in human gliomas

For several years, the cause of autosomal recessive mental retardation has been attributed to the deletion or mutation of a gene named tumor suppressor candidate 3 (TUSC3). Previous research has identified that TUSC3 is a potential tumor suppressor gene in oral epidermoid carcinoma, lung cancer and esophageal cancer. However, to the best of our knowledge, no previously published data has existed on the expression of TUSC3 in gliomas. The present study focused on the expression of TUSC3 in brain gliomas. Additionally, the present study sought to identify he association between TUSC3 expression and the typical clinical and pathological disease manifestations of gliomas. TUSC3 levels were evaluated using a western blot assay and immunohistochemistry on tissue microarray slides. Results indicated a significant decrease in TUSC3 expression in glioma tissues compared with the normal adjacent tissues. Furthermore, TUSC3 expression and World Health Organization grade demonstrated an inverse association in patients with glioma. This revealed that lower levels of TUSC3 in gliomas may be associated with a poorly-differentiated (high grade) tumor and thus a higher malignancy. Through the combination of the results of the present study and future research projects, TUSC3 may be a novel grading tool that assists with evaluating tumor malignancy and consequently a more active therapeutic regimen may be used in patients with glioma.