Yongning Jia

Presence of S100A9-positive inflammatory cells in cancer tissues correlates with an early stage cancer and a better prognosis in patients with gastric cancer

BackgroundS100A9 was originally discovered as a factor secreted by inflammatory cells. Recently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in gastric cancer and explore its role in cancer progression.MethodsS100A9 expression in gastric tissue samples from 177 gastric cancer patients was assessed by immunohistochemistry. The expression of its dimerization partner S100A8 and the S100A8/A9 heterodimer were also assessed by the same method. The effect of exogenous S100A9 on motility of gastric cancer cells AGS and BGC-823 was then investigated.ResultsS100A9 was specifically expressed by inflammatory cells such as macrophages and neutrophils in human gastric cancer and gastritis tissues. Statistical analysis showed that a high S100A9 cell count (> = 200) per 200x magnification microscopic field in cancer tissues was predictive of early stage gastric cancer. High S100A9-positive cell count was negatively correlated with lymph node metastasis (P = 0.009) and tumor invasion (P = 0.011). S100A9 was identified as an independent prognostic predictor of overall survival of patients with gastric cancer (P = 0.04). Patients with high S100A9 cell count were with favorable prognosis (P = 0.021). Further investigation found that S100A8 distribution in human gastric cancer tissues was similar to S100A9. However, the number of S100A8-positive cells did not positively correlate with patient survival. The inflammatory cells infiltrating cancer were S100A8/A9 negative, while those in gastritis were positive. Furthermore, exogenous S100A9 protein inhibited migration and invasion of gastric cancer cells.ConclusionsOur results suggested S100A9-positive inflammatory cells in gastric cancer tissues are associated with early stage of gastric cancer and good prognosis.

WISP-2 in human gastric cancer and its potential metastatic suppressor role in gastric cancer cells mediated by JNK and PLC-γ pathways

Background:It has recently been shown that WISP proteins (Wnt-inducted secreted proteins), a group of intra- and extra-cellular regulatory proteins, have been implicated in the initiation and progression of a variety of tumour types including colorectal and breast cancer. However, the role of WISP proteins in gastric cancer (GC) cells and their clinical implications have not yet been elucidated.Methods:The expression of WISP molecules in a cohort of GC patients was analysed using real-time quantitative PCR and immunohistochemistry. The expression of a panel of recognised epithelial–mesenchymal transition (EMT) markers was quantified using Q-PCR in paired tumour and normal tissues. WISP-2 knockdown (kd) sublines using ribozyme transgenes were created in the GC cell lines AGS and HGC27. Subsequently, several biological functions, including cell growth, adhesion, migration and invasion, were studied. Potential pathways for the interaction of EMT, extracellular matrix and MMP were evaluated.Results:Overexpression of WISP-2 was detected in GC and significantly correlated with early tumour node-metastasis staging, differentiation status and positively correlated with overall survival and disease-free survival of the patients. WISP-2 expression was inversely correlated with that of Twist and Slug in paired samples. Kd of WISP-2 expression promoted the proliferation, migration and invasion of GC cells. WISP-2 suppressed GC cell metastasis through reversing EMT and suppressing the expression and activity of MMP9 and MMP2 via JNK and ERK. Cell motility analysis indicated that WISP-2 kd contributed to GC cells’ motility and can be attenuated by PLC-γ and JNK small inhibitors.Conclusions:Increased expression of WISP-2 in GC is positively correlated with favourable clinical features and the survival of patients with GC and is a negative regulator of growth, migration and invasion in GC cells. These findings suggest that WISP-2 is a potential tumour suppressor in GC.

Apoptosis index correlates with chemotherapy efficacy and predicts the survival of patients with gastric cancer

The objectives of this study are to investigate the apoptotic changes in gastric adenocarcinoma following neoadjuvant chemotherapy and to illuminate its correlation with response. One 67 gastric cancer patients with cT2-4 or TanyN1-3M0 between January 2006 and December 2007 were included. All patients had previous gastrectomy and D2 lymphadenectomy with curative intent performed. A total of 12 cycles of preoperative mFOLFOX7 chemotherapy was recommended for all patients, and 83 patients received only adjuvant chemotherapy. Resected specimens were subjected to in situ TUNEL assay and scanned with Applied Imaging Ariol SL-50. Apoptosis index (AI) was significantly higher in the patient received preoperative chemotherapy (CS group) than in the patient did not (S group). In the CS group, AI was found to have a strong positive correlation with the pathological response (rho = 0.403, P = 0.0002). A ROC curve presented a score of 49.4 as the AI cutoff value for response, dividing the CS group into two subgroups with significantly different prognoses (P = 0.003) and further allowing identification of 8 patients with significantly better prognosis out of 48 patients evaluated as grades 1a–b according to a pathological response evaluation (P = 0.022). In conclusion, AI is correlated with efficacy of preoperative chemotherapy and prognosis of gastric cancer patients following neoadjuvant chemotherapy. An AI cutoff value for response may be used as a complementary approach to current pathological response evaluations to help identify potential responders.

Phosphatase of regenerating liver-3 (PRL-3) is associated with metastasis and poor prognosis in gastric carcinoma

BackgroundPRL-3 is a member of phosphatases of regenerating liver family, characterized by phosphatase active domain and C-terminal prenylation motif. Overexpression of PRL-3 has been implicated in multiple cancers. Here we examined the clinical significance of PRL-3 in gastric cancer together with its metastatic biological functions utilizing different structural mutants.MethodsPRL-3 expression was analyzed immunohistochemically in 196 gastric cancer patients and 21 cases of liver metastasis. A series of wild type PRL-3 or its mutant plasmids were expressed in BGC823 cells to investigate the relationship between its catalytic activity, cellular localization and metastatic potential in vitro.ResultsPositive staining of PRL-3 was observed in 19.4% (38/196) gastric cancer tissues compared with 76.2% (16/21) in liver metastasis. Statistical analysis revealed that PRL-3 expression correlated with lymph node metastasis and vascular invasion (P < 0.05). Patients with high PRL-3 expression showed poorer 5-year overall survival (P = 0.011). Wild type PRL-3 expressing cells resulted in enhanced migration and invasion ability, which were greatly crippled in form of PRL-3(C104S) or PRL-3(ΔCAAX) mutants accompanied with its alteration in subcellular localization.ConclusionsMetastasis associated protein PRL-3 may serve as a potential prognostic biomarker in human gastric cancer. Both the phosphatase catalytic activity and cellular localization are critical for its function.

ABCC2 -24C > T polymorphism is associated with the response to platinum/5-Fu-based neoadjuvant chemotherapy and better clinical outcomes in advanced gastric cancer patients

Several studies have evaluated the efficacy of neoadjuvant treatment using oxaliplatin and fluoropyrimidines in advanced gastric cancer (GC). However, preoperative biomarkers predictive of clinical outcome remain lacking. We examined polymorphisms in the MTHFR, DPYD, UMPS, ABCB1, ABCC2, GSTP1, ERCC1, and XRCC1 genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 103 GC patients treated with preoperative chemotherapy. DNA was extracted from peripheral blood cells, and the genotypes were analyzed using a SNaPShotTM assay, polymerase chain reaction amplification, and sequencing. The ABCC2-24C > T (rs717620) genotype was associated with pathologic response to neoadjuvant chemotherapy. Patients with the TT and TC genotypes responded to neoadjuvant chemotherapy 3.80 times more often than those with the CC genotype (95% CI: 1.27–11.32). Patients with the CC genotype also had poorer outcomes than those with other genotypes. Thus, ABCC2-24C > T polymorphism may help to predict the response to preoperative chemotherapy in GC patients.

Laparoscopic versus open distal gastrectomy for locally advanced gastric cancer after neoadjuvant chemotherapy: safety and short-term oncologic results

BackgroundTo compare the safety and efficacy of laparoscopic distal gastrectomy (LDG) versus open distal gastrectomy (ODG) in treating locally advanced distal gastric cancer after neoadjuvant chemotherapy (NACT).MethodsForty-four patients with locally advanced distal gastric cancer were enrolled. The patients received neoadjuvant chemotherapy before undergoing surgery. Twenty patients were allocated into LDG after NACT group and 24 patients into ODG after NACT group. Radicalness of oncological resection, surgical safety and recovery were measured and compared.ResultsAll operations were successfully performed without severe postoperative complications. There were no significant differences in blood loss, mean operation time, complications, distal and proximal resection margin, and number of retrieved lymph nodes between LDG and ODG groups, but LDG group had shorter length of incision and the first aerofluxus time.ConclusionLaparoscopic distal gastrectomy after NACT has comparable results with open distal gastrectomy in safety and efficacy in the short term.

Death-associated protein-3, DAP-3, correlates with preoperative chemotherapy effectiveness and prognosis of gastric cancer patients following perioperative chemotherapy and radical gastrectomy

Background:DAP3 is a member of the death-associated protein (DAP) family and is characterised by proapoptotic function. It is involved in both exogenous and endogenous apoptotic pathways. In our previous studies, apoptotic level was found to be correlated with the effectiveness of preoperative chemotherapy. The effectiveness of preoperative chemotherapy was also associated with the overall effectiveness of the combined therapy and prognosis. The present study aimed to investigate the role of DAP3 in the evaluation of preoperative chemotherapy effectiveness and its ability to predict prognosis in gastric cancer.Methods:Quantitative PCR and immunohistochemistry staining were performed in 87 patients who received combined therapy. Knockdown of DAP3 was conducted in gastric cancer cell lines to investigate its impact on cell growth, migration, adhesion and invasion. Tolerance to chemotherapy agents was determined by assessing apoptosis and caspase-3.Results:Higher DAP3 expression in gastric tumours was correlated with better prognosis. Knockdown of DAP3 expression promoted cell migration and enhanced resistance to chemotherapy by inhibiting apoptosis.Conclusion:DAP3 is a potential molecular marker for response to preoperative chemotherapy and for predicting prognosis in gastric cancer patients treated with neoadjuvant chemotherapy and gastrectomy.

Hyperthermic intraperitoneal chemotherapy plus simultaneous versus staged cytoreductive surgery for gastric cancer with occult peritoneal metastasis

Our aim is to evaluate the safety and efficacy of two treatment strategies, hyperthermic intraperitoneal chemotherapy (HIPEC) plus simultaneous versus staged cytoreductive surgery (CRS) in patients with occult peritoneal metastasis of gastric cancer (GC).

Clonality analysis of synchronous gastroesophageal junction carcinoma and distal gastric cancer by whole-exome sequencing

Gastro‐oesophageal junction (GEJ) carcinoma and distal gastric cancer (GC) have distinct epidemiology and clinical features and their relationship is uncertain. Synchronous multiple gastric cancers located mostly at proximal and distal sites provide rare specimens for investigating the comprehensive genomic relationships among these cancers in the context of identical genetic circumstances. Formalin‐fixed, paraffin‐embedded (FFPE) samples from 12 patients with synchronous GEJ carcinoma and distal GC were collected in this study. Whole‐exome sequencing (WES) was performed using normal tissues as a control. Mutational profiling, clonality analysis, a detailed clinico‐pathological review, determination of MSI status, EBER in situ hybridization (ISH), and programmed cell death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) immunohistochemical staining were performed. Twenty‐three of the 24 samples were microsatellite‐stable (MSS). Subclonal analysis revealed that nine pairs of GEJ and distal GC tumours in neoadjuvant chemotherapy naïve patients developed independently from different origins. Two patients who received neoadjuvant chemotherapy shared clonal origins with highly similar somatic alterations. The remaining one patient who shared a rare mutation died within 6.2 months at the N3 stage. However, the enriched pathway identified from the overall mutation spectra in distal GC and GEJ carcinoma showed the close relationship of these cancers. Thus, although these cancers may have similar characteristics, histopathological and genetic profiling from single tumour specimens may still underestimate the mutational burden and somatic heterogeneity of multiple GCs. In addition, this series of cases also showed a PD‐L1 expression rate of 58.3% and 66.7% in distal GC and GEJ carcinoma, respectively, with all the cases expressing PD‐1. This result suggests the potential benefit of immunotherapeutic treatments. Copyright

Prognostic value of a 25-gene assay in patients with gastric cancer after curative resection

This study aimed to develop and validate a practical, reliable assay for prognosis and chemotherapy benefit prediction compared with conventional staging in Gastric cancer (GC). Twenty-three candidate genes with significant correlation between quantitative hybridization and microarray results plus 2 reference genes were selected to form a 25-gene prognostic classifier, which can classify patients into 3 distinct groups of different risk of mortality obtained by analyzing microarray data from 78 frozen tumor specimens. The 25-gene assay was associated with overall survival in both training (P = 0.017) and testing cohort (P = 0.005) (462 formalin-fixed paraffin-embedded samples). The risk prediction in stages I + II is significantly better than that in stages III. Analysis demonstrated that this 25-gene signature is an independent prognostic predictor and show higher prognostic accuracy than conventional TNM staging in early stage patients. Moreover, only high-risk patients in stage I + II were found benefit from adjuvant chemotherapy (P = 0.043), while low-risk patients in stage III were not found benefit from adjuvant chemotherapy. In conclusion, our results suggest that this 25-gene assay can reliably identify patients with different risk for mortality after surgery, especially for stage I + II patients, and might be able to predict patients who benefit from chemotherapy.