Constitutive expression of Bcl-2 induces epithelial-Mesenchymal transition in mammary epithelial cells.

BACKGROUND: Bcl-2 (B cell lymphoma/leukemia gene-2) is the first proto-oncogene recognized to function by inhibiting programmed cell death/apoptosis. Although much is known about the anti-apoptotic ability of Bcl-2, little information is available concerning its function in other cellular processes, such as cell differentiation. METHODS: In this study, stable cell lines from pre-malignant MCF10ATG3B mammary epithelial cells, a cell line derived from a human proliferative breast disease model, to express exogenous Bcl-2 was established. CMV promoter driven Bcl-2 expression vector or empty vector was transfected into MCF10ATG3B human mammary epithelial cells to investigate the effects of Bcl-2 on mammary epithelial cells. In addition, western blot and immunofluoresence staining were employed to testify the marker proteins of both mesenchymal and epithelial cells. RESULTS: Unexpectedly, a dramatic change of phenotype from epithelial cells to fibroblast-like cells was observed in Bcl-2-transfected cells. Western blot analysis and immunofluoresence staining results demonstrated that the E-cadherin and desmoplakin, markers of epithelial cells, were downregulated in the Bcl-2-transfected cells. However, N-cadherin and vimentin, markers of mesenchymal cells, were upregulated in these cells. Redistributions of cytokeratin and beta-catenin were also observed in the Bcl-2-transfected cells. Our results further showed that the Bcl-2-transfected MCF10ATG3B cells retained some epithelial markers, such as epithelial specific antigen (ESA) and epithelial membrane antigen (EMA), indicating their epithelial origin. In addition, cell migration and invasion was substantially increased in Bcl-2 transfected cells. CONCLUSION: Taken together, our results strongly indicate that in addition to its anti-apoptotic function, Bcl-2 is also involved in the epithelial-mesenchymal transition (EMT), a fundamental mechanism in normal morphogenesis and pathogenesis of some diseases.

The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma.

To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) in patients with lung adenocarcinoma, the clinical data of 100 patients with pathologically confirmed lung adenocarcinoma and known EGFR mutation status at exon 18, 19, 20, or 21 were analyzed retrospectively. The incidence of BM was similar between patients with wild-type EGFR and those with EGFR mutations (p = 0.48). However, among patients with EGFR mutations, the incidence of BM was significantly higher in patients with mutation at exon 19 than in patients with mutation at other sites (p = 0.007). Besides, among patients with heterochronous BM, 66.7 % had EGFR mutations. Regarding brain-metastasis-free survival (BMFS), patients with EGFR sensitive mutations (mutation at exon 19/21/and dual mutation) had significantly shorter BMFS compared with patients with wild-type EGFR (p = 0.018). For patients treated only with chemotherapy, BM was an unfavorable prognostic factor. Patients with BM had worse overall survival compared with those without BM (p = 0.035). However, in patients with BM and EGFR sensitive mutations, those treated with tyrosine kinase inhibitors (TKIs) had significantly longer overall survival compared with those treated with chemotherapy only (p = 0.0081). In conclusion, among patients with EGFR mutations, those mutated at exon 19 had the highest incidence of BM. Furthermore, patients with EGFR mutations are more likely to develop heterochronous BM. The BMFS was significantly shorter in patients with EGFR sensitive mutations. TKIs improved the survival of patients with lung adenocarcinoma and BM who harbored EGFR sensitive mutations.

A preliminary report on adjuvant analgesic efficacy of HANS in opioid tolerant patients with cancer pain.

OBJECTIVE: To observe the adjuvant analgesic efficacy of Han's Acupoint Nerve Stimulator (HANS) in opioid tolerant patients with cancer pain. METHODS: A prospective non-controlled study was conducted. Opioid tolerant patients with cancer pain were enrolled and treated with both routinely analgesics and adjuvant HANS (2/100 Hz for 30 min/d, 5 d on and 2 d off for two weeks). Cancer pain, quality of life (QOL), anxiety and depression were assessed before enrollment and on d 8 and d 15 with the BPI-C, EORTC QLQ-C30, and self-rating anxiety scale (SAS)/self-rating depression scale (SDS), respectively; the therapeutic frequency of breakthrough pain (BP) and daily opioid dose were also recorded. RESULTS: Totally 47 patients meeting the inclusion criteria participated in this study; 43 patients completed the two-week treatment and assessment. The mean scores of patient's "worst" and "least" pain intensity assessed with BPI-C decreased significantly on d 8 and d 15; the therapeutic frequency of BP also significantly decreased; but the average daily dose of opioids did not change significantly. For the nine symptoms in EORTC QLQ-C30 assessment, the mean scores of pain, fatigue, constipation and insomnia were significantly lower on d 8 and d 15 compared with baseline; the mean scores of the overall health status, nausea/vomiting and the incidence rates of both anxiety and depression also decreased significantly on d 15. CONCLUSIONS: To opioid tolerant patients with cancer pain, adjuvant treatment with HANS could improve pain release and patients' QOL by decreasing the severity of pain, fatigue, constipation, insomnia and other concomitant symptoms; it could also decrease the incidence rates of anxiety and depression.

Multiple genetic variants predict the progression-free survival of bevacizumab plus chemotherapy in advanced ovarian cancer: A retrospective study.

ABSTRACT: Bevacizumab (BV) plus chemotherapy is broadly used in advanced ovarian cancer (OC). However, the efficacy of BV-based regimens for advanced OC patients is not satisfactory. Therefore, it is urgent to explore the predictive genetic biomarkers for BV.Tumor tissues from advanced OC patients receiving BV-based regimens were analyzed with a 150-gene targeted panel for next generation sequencing. The associations between gene alterations or clinicopathology features and progression-free survival (PFS) were analyzed by Kaplan-Meier curves or Cox regression. The association of the genetic alteration in potential predictive genes and expressions of 11 vascular endothelial growth factor-related genes were analyzed in The Cancer Genome Atlas cohort using 292 OC cases.Sixty two Chinese advanced OC patients treated with BV-based therapy were included. The median PFS of was 6.9 months, and objective response rate was 14.5%. In multivariate Cox regression analysis, the status of endothelial growth factor receptor (EGFR) (hazard ratio = 6.39, 95% confidence interval [CI] 2.25-18.13, P < .001) and human epidermal growth factor receptor 2 (HER2) (hazard ratio = 3.58, 95% CI 1.27-10.08, P = .016) were significantly correlated with PFS. MYC Proto-Oncogene amplification seemed to have a positive trend (hazard ratio = 0.21, 95% CI 0.05-1.02, P = .052). Moreover, EGFR and HER2 alterations were not prognostic factors of overall survival for OC in The Cancer Genome Atlas OC cohort. The vascular endothelial growth factor-related signature analysis indicated vascular endothelial factor A expression was upregulated with EGFR alterations (P = .034) which may be involved in BV resistance, and HER2 alterations were associated with hypoxia inducible factor 1 subunit alpha overexpression significantly (P = .029).EGFR or HER2 alterations are negative predictors of PFS for OC patient treated with BV plus chemotherapy. Therefore, the clinicians may consider to use alternative regimens such as anti-EGFR or anti-HER2 targeted therapy instead of BV-based regimens on these patients when standard care fail.

Non-canonical PD-1 signaling in cancer and its potential implications in clinic.

Programmed cell death 1 (PD-1)-based immunotherapy has revolutionized the treatment of various cancers. However, only a certain group of patients benefit from PD-1 blockade therapy and many patients succumb to hyperprogressive disease. Although, CD8 T cells and conventional T cells are generally considered to be the primary source of PD-1 in cancer, accumulating evidence suggests that other distinct cell types, including B cells, regulatory T cells, natural killer cells, dendritic cells, tumor-associated macrophages and cancer cells, also express PD-1. Hence, the response of patients with cancer to PD-1 blockade therapy is a cumulative effect of anti-PD-1 antibodies acting on a myriad of cell types. Although, the contribution of CD8 T cells to PD-1 blockade therapy has been well-established, recent studies also suggest the involvement of non-canonical PD-1 signaling in blockade therapy. This review discusses the role of non-canonical PD-1 signaling in distinct cell types and explores how the available knowledge can improve PD-1 blockade immunotherapy, particularly in identifying novel biomarkers and combination treatment strategies.

A three serum miRNA panel as diagnostic biomarkers of radiotherapy-related metastasis in non-small cell lung cancer.

Serum microRNAs (miRNAs) have been implicated as noninvasive biomarkers for lung cancer diagnosis. However, there are no sensitive and specific biomarkers for the detection of radiotherapy-related non-small cell lung cancer (NSCLC) metastasis. The present study aimed to investigate the role of three serum miRNAs, namely miRNA (miR)-130a, miR-25 and miR-191*, in diagnosing NSCLC, and their biological functions in radiation-mediated development of metastatic properties in A549 cells. To determine this, serum samples were collected from 84 patients with NSCLC and 42 age- and sex-matched healthy controls. Differential expression of serum miRNAs was analyzed by quantitative PCR. Significant associations between miRNA expression and overall survival of patients with NSCLC were identified using the Cox proportional regression model. A receiver operating characteristic curve was generated to evaluate diagnostic accuracy. The functions of miR-130a, miR-25 and miR-191* in lung cancer cells were studied by transfecting A549 cells with miRNA mimics and inhibitors. The results of the present study demonstrated that the expression levels of miR-130a, miR-25 and miR-191* in the serum of patients with NSCLC were increased compared with those in healthy controls, and these increases were associated with advanced age (≥60 years), radiotherapy, histological type (squamous carcinoma), low survival rate and low median survival time. Additionally, irradiation induced the upregulation of miR-130a, miR-25 and miR-191* expression in A549 cells in vitro and in a xenograft mouse model. Irradiation also promoted the invasiveness of A549 cells in vitro and metastasis in vivo. In conclusion, miR-130a, miR-25 and miR-191* may be potential biomarkers for the diagnosis of patients with NSCLC and may serve oncogenic roles in radiation-mediated metastasis of NSCLC.

Serum miR-663 expression and the diagnostic value in colorectal cancer.

Colorectal cancer (CRC) is one of the most common digestive cancers leading to deaths worldwide. In this study, we aimed to investigate the diagnostic value of miR-663 in CRC. The expression of miR-663 was detected by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). The association between miR-663 and clinical parameters of subjects was evaluated by chi-square test. Additionally, ROC (receiver operating characteristic) analysis was performed to evaluate the diagnostic role of miR-663 in CRC. The expression of miR-663 in CRC patients was significantly upregulated compared with benign colorectal disease patients and healthy controls (p < .01). Besides, the expression of miR-663 was significantly associated with tumour differentiation, invasion, lymph node metastasis and TNM stage (p < .05). The cutoff value of miR-663 was 1.31, and the corresponding sensitivity and specificity were 83.1% and 73.8%, respectively. In ROC analysis, the area under the curve (AUC) was 0.806, which indicated that miR-663 could act as an independent diagnostic biomarker for CRC. In conclusion, miR-663 was up-regulated in CRC patients and may be an effective biomarker for CRC diagnosis.

Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation.

OBJECTIVE: This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma. MATERIALS AND METHODS: This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced. (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas, the secondary endpoint was overall survival(OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance was determined using the log-rank test. RESULTS: The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. CONCLUSION: Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR.sensitive mutation.

Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation.

OBJECTIVE: This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma. PATIENTS AND METHODS: This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance were determined using the log-rank test. RESULTS: The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. CONCLUSION: Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR-sensitive mutation.