[Show abstract][Hide abstract] ABSTRACT: Fas signaling-activated signal transducers and activators of transcription 3 (STAT3) is required for Fascin upregulation. As an actin-bundling protein, Fascin can mediate gastric cancer (GC) cell migration.
Gastric cancer AGS cells were treated with anti-Fas (5 μg/ml) for 2 h, in order to stimulate the activation of the Fas signaling. The in vitro migration of Fas signaling-activated AGS cells was assessed using Transwell chambers. The levels of Fascin and phosphorylated STAT3 were detected by Western blotting analyses. Nude mice were injected intravenously with AGS cells treated with anti-Fas or treated with STAT3 inhibitor without anti-Fas; tumor pulmonary metastases were measured. Fascin protein expression in tumor tissues was detected by immunohistochemistry. The Fas and Fascin mRNA levels in tumor tissues from patients with GC were measured by real-time PCR and their correlation was analyzed.
The activation of Fas signaling promoted cell migration and resulted in STAT3-dependent Fascin upregulation in AGS cells. STAT3 enhanced Fascin levels in vivo. Fascin was the mediator of Fas signaling-induced AGS cell migration in vitro and in vivo. Furthermore, there was a positive correlation between Fas and Fascin mRNA levels in tumor tissues from GC patients.
Fas signaling promotes GC metastasis through the STAT3/Fascin pathway, which may provide a new target for GC therapy.
PLoS ONE 05/2015; 10(5):e0125132. DOI:10.1371/journal.pone.0125132 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumour-cell-derived exosomes (Exo) have been proposed as a new kind of drug carrier, and heat stress can promote release of exosomes from tumour cells. This study investigated the impact of heat stress on the quantity of doxorubicin in exosomes from the same number of doxorubicin-treated MFC-7 tumour cells and their anti-tumour effects.
Exosomes were isolated from phosphate-buffered saline (Exo), doxorubicin (Exo-Dox) or doxorubicin combined with heat-stress-treated (Exo-Dox-HS) MCF-7 cells. The content of doxorubicin in the exosomes was determined by flow cytometry. The effects of individual types of exosomes on the MCF-7 cell proliferation and apoptosis as well as the tumour growth were determined by MTT assay, flow cytometry and murine xenograft tumour modelling.
We found that the amount of Exo-Dox-HS was higher than that of Exo-Dox from the same number of MCF-7 cells, and Exo-Dox-HS contained higher levels of doxorubicin than Exo-Dox from the same number of cells. Exo-Dox and Exo-Dox-HS, but not Exo or 10 µg/mL doxorubicin, significantly inhibited the MCF-7 cell proliferation and triggered MCF-7 cell apoptosis, associated with increased levels of cleaved caspase-3 and -8 and morphological changes in MCF-7 cells. Treatment with Exo-Dox and Exo-Dox-HS inhibited the growth of implanted breast tumours in mice.
Our study indicated that heat stress increased the quantity of doxorubicin-containing exosomes from tumour cells, and enhanced the anti-tumour effect of exosomes from the doxorubicin-treated tumour cells. Our findings may aid in designing new strategies for cancer therapy by combination of chemotherapy and hyperthermia.
International Journal of Hyperthermia 05/2015; 31(5):1-9. DOI:10.3109/02656736.2015.1036384 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the levels of D-dimer baseline levels in inoperable metastatic colorectal cancer (mCRC) patients treated with bevacizumab and its relationship with prognosis.
From June 1, 2011 to December 31, 2013, a total of 121 patients with mCRC received beacizumab combined with chemotherapy and 74 of them were included in the present study. A nonparametric statistical test was performed to analyze the relationship between plasma D-dimer levels and clinical pathological factors. The Cox proportional model was used to analyze the effects of D-dimer on progression-free survival (PFS) time and overall survival (OS).
Of the 74 cases, 40 were men and 34 women (aged 31-74 years), with a median age of 55.5 years. The median of PFS and OS were 6.3 and 17.8 months respectively. High levels of baseline plasma D-dimer were correlated with high scoring of Eastern Cooperative Oncology Group-Performance Status (P = 0.001), IV phase of disease at the first visit (P = 0.001), unremoval primary focal (P = 0.006), the number of metastatic organs ≥ 2 (P = 0.034), abdominal cavity effusion (P = 0.004) and no history of adjuvant chemotherapy (P = 0.003). It was found by single factor analysis that plasma baseline D-dimer levels ≥ 1.9 μg/mL were closely related with a short PFS (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.04-4.40, P = 0.038) and OS (HR 5.22, 95% CI 2.05-13.28, P = 0.001). After adjustment for other factors, plasma baseline D-dimer levels ≥ 1.9 μg/mL were still closely correlated with a short OS (HR 3.52, 95% CI 1.28-9.67, P = 0.015).
High levels of plasma baseline D-dimer correlated with high tumor load, advanced disease status and poor prognosis of inoperable mCRC patients treated with bevacizumab. However, clinical research on a much larger cohort of patients will be required to verify these findings.
Journal of Cancer Research and Therapeutics 12/2014; 10 Suppl(8):246-51. DOI:10.4103/0973-1482.151451 · 0.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemotherapy is of crucial importance in advanced gastric cancer (AGC) patients, in order to obtain palliation of symptoms and improve survival. To date, no standard chemotherapy regimen has been established for AGC. The purpose of the present study was to evaluate the efficacy and toxicity of the combination regimen of paclitaxel and capecitabine (PX) as first-line chemotherapy in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated with PX as first-line chemotherapy between January 2001 and December 2012 at the Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. In total, 36 patients were enrolled, with a median age of 53.5 years and a Karnofsky performance status (KPS) score of ≥80. A median of 4 PX cycles were administered (range, 2-8 cycles). The median progression-free survival time was 3.7 months [95% confidence interval (CI), 2.9-4.5 months) and the median overall survival time was 12.0 months (95% CI, 9.8-14.1 months). From the 36 patients evaluated, one (2.8%) achieved a complete response, seven (19.4%) achieved a partial response, 24 (66.7%) exhibited stable disease and four (11.1%) exhibited progressive disease. The objective response rate was 22.2% (8/36), and the disease control rate was 88.9% (32/36). All 36 patients were assessed for treatment toxicity. Grade 3 or 4 adverse events included neutropenia (2.8% of patients), hand-foot syndrome (2.8%) and vomiting (2.8%). No neutropenic fever or treatment-related mortalities were observed. PX combination chemotherapy may be a valuable first-line therapy for advanced or recurrent gastric cancer.
[Show abstract][Hide abstract] ABSTRACT: Cervical regional nodal involvement, as the first manifestation of prostatic cancer, has been rarely reported. Prostate cancer metastasis to the supraclavicular lymph nodes with negative immunohistochemical stain of PSA is even rarer. We report a case of prostate cancer with negative immunohistochemical stain of prostate-specific antigen presenting with left supraclavicular node enlargement. A 63-year-old man was referred to our hospital for a left supraclavicular mass. He had a family history of gastric cancer (two brothers had died of gastric cancer). Enhanced computed tomography of the abdomen revealed retroperitoneal lymph node enlargement. Gastroscopy revealed no evidence of any gastric tumor. Biopsy of the left-sided supraclavicular lymph nodes revealed metastatic adenocarcinoma with a negative prostate-specific antigen (PSA) stain. The serum tumor markers were examined, revealing PSA levels of 21.820 ng/ml. Biopsy of the prostate disclosed poorly-to-moderately differentiated adenocarcinoma (Gleason 4 + 4 = 8).
Although rare, prostate cancer should be considered in the differential diagnoses of elderly men with undetermined original adenocarcinoma, metastatic to the supraclavicular lymph nodes. Rectal examination, serum PSA and pelvic image can be helpful to lead the diagnosis. PSA stain may be weak or negative in some poorly differentiated patients, however, it is still a sensitive and specific marker of prostatic differentiation and must be routinely applied.
Journal of research in medical sciences 09/2013; 18(9):814-7. · 0.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/Aims: To evaluate the efficacy and safety profile of S-1 combined with oxaliplatin (SOX) against unresectable advanced or metastatic gastric cancer. Methodology: Oxaliplatin was administered intravenously at 100mg/m2 for two hours on day 1 and S-1 was administered b.i.d. at 80mg/m2/day on days 1-14 followed by a 7-day rest during the 3-week schedule. Results: All 51 patients were assessed for efficacy and adverse events. The response and disease control rates were 41% and 90%, respectively. The response rate was significantly improved in patients with ECOG performance status of no more than 1, elevated CEA levels or unresected primary cancers. The median follow-up time was 11.8 months, the median time to progression was 6.8 months, the median overall survival was 11.8 months and the 1-year survival rate was 47.4%. Patients with diffused type exhibited significantly decreased time to progression and overall survival. The grade 3/4 adverse events were hematological toxicities, including neutropenia (13.7%), thrombocytopenia (13.7%) and anemia (11.8%). The incidence of grade 3/4 non-hematological events was low (≤2%). Conclusions: The SOX regimen (oxaliplatin, 100mg/m2 d1; S-1, 80mg/m2/day, b.i.d. d1-14, q3w) provided a favorable efficacy and safety profile in Chinese patients with advanced gastric cancer.
[Show abstract][Hide abstract] ABSTRACT: Tumour cell-derived exosomes may represent a novel type of cancer vaccine. However, the immunogenicity of exosomes derived from tumour cells has been shown to be poor. Therefore, in this study, exosome immunogenicity following heat treatment of exosomes from malignant ascites obtained from gastric cancer patients was evaluated.
Tumour-derived exosomes were isolated from heat-treated and untreated malignant ascites of gastric cancer patients using serial centrifugation and sucrose gradient ultracentrifugation. Next, in vitro experiments were performed to investigate the influence of heat treatment on exosome immunogenicity.
Exosomes from heat-treated malignant ascites of gastric cancer patients (HS exosomes) were found to contain higher concentrations of heat shock proteins, Hsp70 and Hsp60, than exosomes derived from untreated malignant ascites obtained from gastric cancer patients. Additional in vitro studies suggest that exosomes derived from heat-treated malignant ascites are able to promote dendritic cell (DC) maturation and induce a tumour-specific cytotoxic T lymphocyte (CTL) response.
Overall, these results demonstrate that exposure to heat stress can improve the immunogenicity of exosomes obtained from malignant ascites of gastric cancer patients.
International Journal of Hyperthermia 09/2011; 27(6):604-11. DOI:10.3109/02656736.2011.564598 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inhibition of calcium/calmodulin-dependent protein kinase II (CaMKII) results in hypophosphorylation of CaMKII substrates and in some cases suppresses cell growth. We previously presented the first report of the human CaMKII inhibitory protein, hCaMKIINbeta. Here we report the functional characterization of hCaMKIINbeta in ovarian cancer cells. We showed that hCaMKIINbeta was highly expressed in normal ovarian tissues but was not detected in human ovarian adenocarcinoma, indicating that decreased expression of hCaMKIINbeta may be involved in the pathogenesis of human ovarian adenocarcinoma. As an endogenous CaMKII inhibitor, hCaMKIINbeta could significantly inhibit the growth of human ovarian cancer cells in vitro. In vivo, hCaMKIINbeta decreased the tumorigenicity and growth of HO-8910PM human ovarian cancer cells and prolonged the survival of tumor-bearing mice. hCaMKIINbeta blocked cell cycle progression and induced apoptosis of HO-8910PM cells, which was correlated with the up-regulation of p21, p53, and Bax and the down-regulation of cyclin A, cyclin D1, cyclin E, CDK2, phosphorylated retinoblastoma, and Bcl-2. We further demonstrated that hCaMKIINbeta-mediated CaMKII inhibition suppressed Akt activation, leading to the down-regulation of HDM2, which was responsible for the up-regulation of p53 and p21 in human ovarian cancer cells. The tumor-suppressive effect and the negative expression in human ovarian cancer tissues suggest that hCaMKIINbeta may play an important role in the regulation of tumor cell growth, possibly contributing to the development of new therapeutic strategies for ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: This study is performed to evaluate the response rate, time to progression and safety of the combination chemotherapy with weekly paclitaxel plus cisplatin in advanced gastric and gastro-esophageal cancer.
The paclitaxel 100 mg/m(2) was administered through a 1 h intravenous infusion on Days 1 and 8. The cisplatin 30 mg/m(2) was also administered along with a program of forced diuresis that included at least 2000 ml of fluids after the paclitaxel infusion over 30 min on Days 1 and 8. The chemotherapy was given every 21 days and continued until disease progression, patient refusal or an unacceptable toxicity up to nine cycles.
Forty-seven (95.9%) of the 49 patients were assessable for response. Two cases of complete response and 19 cases of partial response were confirmed, giving an overall response rate of 42.9% (95% CI, 29.0-56.8%). The median time to progression and overall survival for all patients were 5.9 months (95% CI, 1.6-9.1 months) and 11.2 months (95% CI, 6.1-21.3 months). The most severe hematologic adverse event was neutropenia, which occurred with a Grade 3 intensity in 17.0% and Grade 4 in 4.3%. Grade 3 vomiting, peripheral neuropathy and elevated transaminase were observed in 4.3%, 4.3% and 2.1% of patients.
Combination of weekly paclitaxel plus cisplatin is an active regimen with excellent tolerability as a first-line treatment of advanced gastric and gastro-esophageal cancer.
Japanese Journal of Clinical Oncology 05/2009; 39(4):237-43. DOI:10.1093/jjco/hyp008 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The fluoropyrimidine and platinum-based combination chemotherapy is now widely used as first-line therapy for advanced gastric cancer (AGC). Unfortunately, about half of all patients do not respond to the current first-line chemotherapy and furthermore, most patients who achieve response to first-line chemotherapy eventually experience disease progression. Although there is a need for effective salvage treatment after the failure of first-line chemotherapy, data on the safety and efficacy of second-line treatment in AGC is limited. The current study evaluated an experimental combination regimen of docetaxel (60 mg/m) as an intravenous infusion of less than 1 h, followed by oxaliplatin (130 mg/m) intravenously for less than 2 h. Both drugs were administered on day 1 of a 21-day cycle, in pretreated Chinese patients with AGC. The trial enrolled 48 patients of whom 46 (95.8%) were assessable for response. The median time to progression was 4.4 months (95% confidence interval (CI): 3.4-5.4 months) and the median overall survival was 7.2 months (95% CI: 6.6-12.1 months). Partial response was confirmed in 11 of 48 cases (22.9%; 95% CI: 10.9-34.9%) and no complete responses were seen. Significant hematologic toxicity was noted with grade 3 and grade 4 neutropenia occurring in 21.7 and 4.3% of patients, respectively, as well as grade 3 thrombocytopenia occurring in 4.3% of patients. Grade 3 febrile neutropenia occurred in 6.5% of the patients. There were no treatment-related deaths during on the study. In summary, docetaxel and oxaliplatin have modest activity with predictable hematologic toxicity when given as salvage therapy for Chinese patients treated earlier for AGC. Given the short duration of response more focus should be given to newer biologic agents and triplet regimens.