OBJECTIVEs To investigate the relationship between the expression of VEGF-C, VEGFR-3 and lymph node metastasis (LNM) in the gastric cancer, and explore the role of VEGF-C, VEGFR-3 in the prognosis of gastric cancer.

METHODSGastric cancer specimens were selected from gastric cancer database from April, 1994 to December, 2003, which were registered and followed up. The specimens were divided into two groups according to LNM existing or not. Immunohistochemistry staining was performed with anti-VEGF-C, anti-VEGFR-3 monoclonal antibody by DAB method. Their effects on prognosis of gastric cancer patients were analyzed by Kaplan-meier, Logistic and Cox Regression methods.

RESULTSIn 188 cases of gastric cancer patients, 97 patients presented with LNM and the rest did not. The positive expression rate of VEGF-C, VEGFR-3 in the group without LNM was lower than those in group with LNM, and there was significant difference between the two groups. There was significant difference in the average lymphatic vessel density between the group with LNM and the group without, and the same results were found between the group with positive VEGF-C expression and the group without.

CONCLUSIONSVEGF-C, VEGFR-3 are over-expressed in gastric cancer patients with LNM, and the expression of VEGF-C, VEGFR-3 are important predictors for the prognosis of gastric cancer.

Humans ; Lymph Nodes ; pathology ; Lymphangiogenesis ; Lymphatic Metastasis ; Prognosis ; Stomach Neoplasms ; metabolism ; mortality ; pathology ; Survival Rate ; Vascular Endothelial Growth Factor C ; metabolism ; Vascular Endothelial Growth Factor Receptor-3 ; metabolism

The aim of the present study was to accurately evaluate the association of Sox2 expression with the survival of patients with digestive tract cancers. Relevant literatures were identified by comprehensively searching databases including the Pubmed, Embase, CBMdisc, and Wanfang (up to October 2014). A meta-analysis was performed to clarify the association between Sox2 expression and overall survival or clinicopathological parameters of patients with digestive tract cancers (esophageal, gastric, and colorectal cancers). The results showed a significant association between high Sox2 expression and poor overall survival in patients with digestive tract carcinomas (HR=1.55, 95% CI=1.04-2.31), especially for patients with esophageal cancer (HR=2.04, 95%CI=1.30-3.22), colorectal cancer (HR=1.40, 95% CI=1.04-1.89), and digestive tract adenocarcinoma (HR=1.80, 95% CI=1.12-2.89), for Europeans (HR=1.98, 95% CI=1.44-2.71) or patients who did not receive neoadjuvant treatment (HR=1.73, 95% CI=1.10-2.72). Furthermore, Sox2 over-expression was highly correlated with vascular invasion (OR=1.86, 95% CI=1.25-2.77) and poor differentiation (OR=1.88, 95% CI=1.14-3.08), especially in esophageal and colorectal cancers. In conclusion, Sox2 expression may serve as a novel prognostic factor for patients with digestive tract cancers. Over-expression of Sox2 that is correlated with vascular invasion and poor differentiation suggests poor outcomes of patients with digestive tract cancers.
Antineoplastic Agents ; therapeutic use ; Biomarkers, Tumor ; genetics ; metabolism ; Colorectal Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Esophageal Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Gastrointestinal Tract ; metabolism ; pathology ; Gene Expression ; Humans ; Neoadjuvant Therapy ; methods ; Neoplasm Grading ; Neoplasms, Vascular Tissue ; diagnosis ; drug therapy ; mortality ; secondary ; Prognosis ; SOXB1 Transcription Factors ; genetics ; metabolism ; Stomach Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Survival Analysis

BACKGROUND/AIMS: Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a recently clarified tumor suppressor gene located in 10q23.3. Alterations of this gene are associated with tumor progression and unfavorable outcome in various human cancers. Recently, PTEN has a possible role in angiogenesis by modulating angiogenic factor including vascular endothelial growth factor (VEGF). The aim of this study was to investigate the roles of PTEN and VEGF status for angiogenesis in human gastric cancer. METHODS: We conducted an immunohistochemical investigation of PTEN and VEGF expression in 90 cases of paraffin section obtained from gastric cancer patients undergone surgical treatment. RESULTS: Negative expression of PTEN and positive expression of VEGF in gastric cancer tissues, were demonstrated in 40.0% and 77.8% of cases, respectively. However, no significant correlation was found between PTEN, VEGF expression and various clinicopathological parameters. PTEN expression did not correlate significantly with VEGF expression (p=0.301). High microvessel density (MVD) was significantly associated with lymph node metastasis and poor survival (p=0.014, 0.011, respectively). The mean MVD value of PTEN negative tumors was 90.4+/-43.0 and significantly higher than that of PTEN positive tumors (p=0.028). The mean MVD value of VEGF positive tumors was 86.4+/-36.7 and significantly higher than that of VEGF negative tumors (p=0.002). The mean MVD value of PTEN negative and VEGF positive tumors was 98.0+/-42.2, and significantly higher than those of the others. CONCLUSIONS: These results suggest that loss of PTEN expression may play a critical role in tumor progression and metastasis by stimulating tumor angiogenesis in human gastric cancer.
Adult ; Aged ; Carcinoma/*blood supply/metabolism/mortality/secondary ; Disease Progression ; Female ; Humans ; Immunohistochemistry ; Male ; Microcirculation/pathology ; Middle Aged ; Neovascularization, Pathologic/*metabolism ; PTEN Phosphohydrolase/*metabolism ; Stomach Neoplasms/*blood supply/metabolism/mortality ; Survival Rate ; Vascular Endothelial Growth Factor A/metabolism

BACKGROUNDThis study was to evaluate bivariate bromodeoxyuridine (BrdUrd)/DNA flow cytometric analysis in detection of gastric carcinoma and to study the relations of cellular BrdUrd labeling indices (LI), G2/M-phase fraction (G2/MPF) and DNA ploidy pattern to lymphatic involvement, venous invasion and prognosis.

METHODSFresh tumor samples from 60 patients with gastric carcinoma were analyzed by bivariate BrdUrd/DNA flow cytometry. The results were correlated with lymphatic vessel invasion, lymphatic node metastasis, the number of metastatic lymphatic nodes, and venous invasion. Propidium iodide (PI) was used as a fluorescent probe for total cellular DNA, and a monoclonal antibody against BrdUrd was used as a probe for BrdUrd incorporated into DNA. Fluorescent-labeled goat anti-mouse antibody was used as a second antibody. S-phase fractions were measured by in vitro BrdUrd labeling, and DNA ploidy and G2/MPF were also measured. Comparison of survival was performed with the log-rank test, the Chi-square test for qualitative data, and Student's t test for quantu data.

RESULTSBrdUrd LI and G2/MPF values were significantly higher in tumors with lymphatic vessel invasion than in those without invasion respectively (P < 0.01); the patients who had tumors with lymphatic vessel invasion showed a significantly poor prognosis (P < 0.01). Both BrdUrd LI and G2/MPF values were significantly higher in tumors with lymphatic node metastasis than in those without metastasis (P < 0.01). A statistical significant difference was noted in the 5-year survival rates between the patients with lymph node metastasis and those without metastasis. Compared with diploid carcinoma, the incidence of lymph node metastasis was significantly higher in aneuploid carcinoma (P < 0.05), and the patients with aneuploid carcinoma showed a significantly poor prognosis (P < 0.05). BrdUrd LI was significantly higher in patients with more than 5 metastatic lymph nodes than those with 1 - 4 metastatic lymph nodes (P < 0.05) and those without metastasis (P < 0.01). G2/MPF values in those patients either with more than 5 metastatic lymph nodes or 1 - 4 metastatic lymph nodes were higher than those without metastasis (P < 0.01 and P < 0.05). A statistical significance was seen in the 5-year survival rates among the patients with no metastatic lymph node, 1 - 4 metastatic nodes and more than 5 metastatic nodes (P < 0.01). G2/MPF values were significantly higher in patients with venous invasion than in those without invasion (P < 0.01).

CONCLUSIONSPositive correlations exist between cellular BrdUrd LI, G2/MPF with lymphatic involvement and prognosis, and DNA aneuploid with lymphatic involvement and prognosis. The same was true between G2/MPF value and venous invasion in gastric carcinoma.

Adult ; Aged ; Bromodeoxyuridine ; metabolism ; Cell Cycle ; Cell Division ; Female ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Ploidies ; Prognosis ; Stomach Neoplasms ; mortality ; pathology ; Survival Rate

Thymidine phosphorylase (TP) has shown to be up-regulated in several cancers and to play a role in angiogenesis and invasion. Most studies regarding TP have focused on cancer cells. Recently, evidences suggest that TP in cancer-infiltrating inflammatory cells (CIICs) also affect the cancer cell behavior. To evaluate the significance of TP expression of CIICs in gastric cancer, we assessed TP expression of cancer cells and CIICs separately using immunohistochemical assay on 116 paraffin-embedded tissue samples from stomach cancer patients and investigated their clinical significance. When subjects were divided into 4 groups according to the TP expression: cancer/matrix (+/+), C/M (+/-), C/M (-/+), and C/M (-/-), intratumoral microvessel density scores were higher in the C/M (+/-) group than in the C/M (-/-) group (p=0.02). For lymph node metastasis and survival, there were no significant differences among the 4 groups. However, there were significant differences in survival (p=0.035) and LN metastasis (p=0.023) between the two groups divided by TP expression of CIICs alone irrespective of TP expression of cancer cells. Taken together, this study suggested the TP expression in CIICs could affect lymph node metastasis and patients' survival in gastric cancer.
Adult ; Aged ; Female ; Humans ; Immunohistochemistry ; Inflammation/*enzymology/pathology ; Kaplan-Meiers Estimate ; Lymphatic Metastasis ; Lymphocytes, Tumor-Infiltrating/*enzymology/pathology ; Male ; Microcirculation/pathology ; Middle Aged ; Neovascularization, Pathologic ; Prognosis ; Stomach Neoplasms/blood supply/*enzymology/mortality/pathology ; Thymidine Phosphorylase/*metabolism

Although N-myc downstream regulated gene 2 (NDRG2) has been known to be a tumor suppressor gene, the function of this gene has not been elucidated. In the present study, we investigated the expression and function of NDRG2 in human gastric cancer. Among seven gastric cancer and two non-cancer cell lines, only two gastric cancer cell lines, SNU-16 and SNU-620, expressed NDRG2, which was detected in the cytoplasm. Interestingly, NDRG2 was highly expressed in normal gastric tissues, but gastric cancer patients were divided into NDRG2-positive and -negative groups. The survival rate of NDRG2-negative patients was lower than that of NDRG2-positive patients. We confirmed that the loss of NDRG2 expression was a significant and independent prognostic indicator in gastric carcinomas by multivariate analysis. To investigate the role of NDRG2 in gastric cancer cells, we generated a NDRG2-silenced gastric cancer cell line, which stably expresses NDRG2 siRNA. NDRG2-silenced SNU-620 cells exhibited slightly increased proliferation and cisplatin resistance. In addition, inhibition of NDRG2 decreased Fas expression and Fas-mediated cell death. Taken together, these data suggest that inactivation of NDRG2 may elicit resistance against anticancer drug and Fas-mediated cell death. Furthermore, case studies of gastric cancer patients indicate that NDRG2 expression may be involved in tumor progression and overall survival of the patients.
Apoptosis/*physiology ; Cell Line, Tumor ; Down-Regulation ; Fas Ligand Protein/*physiology ; Gene Expression Regulation, Neoplastic ; Humans ; Stomach Neoplasms/metabolism/*mortality/pathology ; Tumor Markers, Biological/*metabolism ; Tumor Suppressor Proteins/biosynthesis/genetics/immunology/*metabolism

OBJECTIVETo investigate mRNA expression of syndecan-1 and heparanase in gastric carcinoma, and their correlation with the growth-pattern, invasion, metastasis and prognosis of gastric carcinoma.

METHODSIn situ hybridization technique was used to examine mRNA expression of syndecan-1 and heparanase in 118 specimens of gastric carcinoma.

RESULTSThe positive rates of syndecan-1 mRNA and heparanase mRNA were 42.4% and 55.9%, respectively. The expression of syndecan-1 mRNA and heparanase mRNA were related to tumor invasion depth (chi(2) = 32.95, P = 0.001; chi(2) = 23.19, P = 0.001), vessel invasion (chi(2) = 46.22, P = 0.001; chi(2) = 33.78, P = 0.001), lymph node (chi(2) = 28.62, P = 0.001; chi(2) = 25.43, P = 0.001) and distant metastasis (chi(2) = 63.30, P = 0.001; chi(2) = 65.76, P = 0.001), and syndecan-1 mRNA positive expression was related to tumor size (chi(2) = 6.25, P = 0.012). There was a negative relationship between Syndecan-1 mRNA and heparanase mRNA expression (r = -0.844, P = 0.001). The mean survival time of cases with low expression of syndecan-1 mRNA was significantly shorter than that of cases with high expression (r = 36.48, P = 0.001), and meanwhile, the mean survival time of heparanase mRNA positive cases was significantly shorter than that of cases with negative expression (r = 34.41, P = 0.001).

CONCLUSIONSThe mRNA expression of syndecan-1 and heparanase can predict the invasion and metastasis of gastric carcinoma, and can be used as markers of prognosis of gastric carcinoma.

Adult ; Aged ; Female ; Follow-Up Studies ; Glucuronidase ; genetics ; metabolism ; Humans ; In Situ Hybridization ; Lymphatic Metastasis ; Male ; Middle Aged ; RNA, Messenger ; genetics ; Stomach Neoplasms ; metabolism ; mortality ; pathology ; Survival Rate ; Syndecans ; genetics ; metabolism

OBJECTIVETo investigate the expression of osteopontin (OPN) splice variant mRNA, including the three isoforms OPN-A, OPN-B, and OPN-C, to explore its correlation with clinicopathologic features in gastric cancer, and to elucidate their role in tumor invasion and distant metastasis of gastric cancer.

METHODSThe expression of OPN-A, OPN-B and OPN-C mRNA were detected by real-time reverse transcriptase-polymerase chain reaction in 66 gastric cancer tissues. The relationship between the expression of OPN-A, OPN-B and OPN-C mRNA and clinicopathologic features of gastric cancer was analyzed.

RESULTSThe expression of OPN-C mRNA in the gastric cancer tissue was 3.21-fold higher than that in peritumoral mucosal tissue, showing a significant difference between them (P < 0.001). OPN-C mRNA expression was correlated with the depth of tumor invasion, tumor diameter, lymph node meatastasis, distant meatastasis and had no correlation with differentiation grades. The low expression of OPN-C mRNA was correlated with long survival benefit (P = 0.03). The expression of OPN-A and OPN-B mRNA had no significant relationship with clinicopathologic features of gastric cancer.

CONCLUSIONSOne of the isoform of osteopontin (OPN) OPN-C mRNA is overexpressed in gastric cancer. The overexpression of OPN-C mRNA may reflect the progression and is associated with the prognosis of gastric cancer. OPN-C mRNA may have value as a prognostic biomarker in gastric cancer. However, the expression of OPN-A and OPN-B are not correlated with the progression and metastasis of gastric cancer.

Disease Progression ; Gastric Mucosa ; metabolism ; Humans ; Lymph Nodes ; Lymphatic Metastasis ; Neoplasm Invasiveness ; Neoplasm Proteins ; genetics ; Osteopontin ; genetics ; Prognosis ; Protein Isoforms ; genetics ; RNA, Messenger ; metabolism ; Real-Time Polymerase Chain Reaction ; Stomach Neoplasms ; genetics ; mortality ; pathology

Adenocarcinoma ; blood supply ; metabolism ; mortality ; secondary ; Adult ; Aged ; Female ; Humans ; Lymphatic Metastasis ; Male ; Microcirculation ; Middle Aged ; Neovascularization, Pathologic ; metabolism ; pathology ; Prognosis ; RNA, Messenger ; biosynthesis ; genetics ; Receptors, Cell Surface ; biosynthesis ; genetics ; Receptors, Urokinase Plasminogen Activator ; Stomach Neoplasms ; blood supply ; metabolism ; mortality ; pathology ; Survival Rate ; Vascular Endothelial Growth Factor A ; metabolism

BACKGROUND/AIMS: Several studies reported a subgroup of gastric cancer patients showing elevated serum alpha-fetoprotein (AFP) at the time of diagnosis. We investigated the clinicopathological characteristics and prognostic factors of AFP producing gastric cancer (AFPPGC) by comparing with AFP non-producing gastric cancer (AFPNPGC). METHODS: A total of 909 patients were diagnosed with gastric cancer from January 2005 to March 2013 at Gyeongsang National University Hospital and their AFP levels were measured at the time of diagnosis. After excluding 138 patients with underlying liver diseases, 34 patients with elevated serum AFP level over 10 mg/mL were assigned to AFPPGC group and the remaining 737 patients with serum level of AFP below 10 ng/mL were assigned to AFPNPGC group. RESULTS: The median survival length was shorter in AFPPGC group than AFPNPGC group (18.3+/-25.5 months vs. 30.0+/-22.0 months, p=0.004). The incidence of liver metastasis (47.1% vs. 3.3%, p<0.001) and lymph node metastasis (91.2% vs. 31.6%, p<0.001) was significantly higher in AFPPGC group. The probability of encountering metachronous liver metastasis after the operation was higher in AFPPGC group (44.4% vs. 2.0%, p<0.001). Multivariate analysis revealed that patients in the AFPPGC group who received chemotherapy (p=0.037) or underwent operation (p=0.001) had a better survival rate. CONCLUSIONS: AFPPGC behaves more aggressively and shows a worse prognosis. Therefore, serum AFP level should be routinely checked in all patients diagnosed with gastric cancer.
Aged ; Aged, 80 and over ; Female ; Humans ; Liver Neoplasms/secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Smoking ; Stomach Neoplasms/*diagnosis/mortality/pathology ; Survival Rate ; Treatment Outcome ; alpha-Fetoproteins/*metabolism