Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathophysiology of Helicobacter pylori-associated gastroduodenal diseases, ulcerogenesis, and carcinogenesis is intimately linked to activation of epidermal growth factor receptor (EGFR) and production of vascular endothelial growth factor (VEGF). Extracellular virulence factors, such as CagA and VacA, have been proposed to regulate EGFR activation and VEGF production in gastric epithelial cells. We demonstrate that the H. pylori secretory protein, HP0175, by virtue of its ability to bind TLR4, transactivates EGFR and stimulates EGFR-dependent VEGF production in the gastric cancer cell line AGS. Knock-out of the hp0175 gene attenuates the ability of the resultant H. pylori strain to activate EGFR or to induce VEGF production. HP0175-induced activation of EGFR is preceded by translocation of TLR4 into lipid rafts. In lipid rafts, the Src kinase family member Lyn interacts with TLR4, leading to tyrosine phosphorylation of TLR4. Knockdown of Lyn prevents HP0175-induced activation of EGFR and VEGF production. Tyrosine-phosphorylated TLR4 interacts with EGFR. This interaction is necessary for the activation of EGFR. Disruption of lipid rafts with methyl beta-cyclodextrin prevents HP0175-induced tyrosine phosphorylation of TLR4 and activation of EGFR. This mechanism of transactivation of EGFR is novel and distinct from that of metalloprotease-dependent shedding of EGF-like ligands, leading to autocrine activation of EGFR. It provides new insight into our understanding of the receptor cross-talk network.
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PMID:Helicobacter pylori protein HP0175 transactivates epidermal growth factor receptor through TLR4 in gastric epithelial cells. 1880 58

Accurate prediction of lymph node (LN) status is of crucial importance for appropriate treatment planning in patients with early gastric cancer (EGC). However, there is no definitive consensus yet on which patient and/or tumor characteristics are associated with LN metastasis. A systematic search for studies investigating the relationship between patient and/or tumor characteristics and LN metastasis in EGC was performed in PubMed/MEDLINE. Patient and/or tumor characteristics associated with LN metastasis were identified by meta-analyzing results of individual studies. Forty-five studies were included. Variables significantly associated with LN metastasis in gastric cancer limited to the mucosa were: age younger than 57 years, tumor location in the middle part of the stomach, larger tumor size, macroscopically depressed tumor type, tumor ulcerations, undifferentiated tumors, diffuse tumor type according to the Lauren classification, lymphatic tumor invasion, tumors with a proliferating cell nuclear antigen (PCNA) labeling index of more than 25%, and matrix metalloproteinase-9-positive tumors. Variables significantly associated with LN metastasis in gastric cancer limited to the submucosa were: female sex, tumor location in the lower part of the stomach, larger tumor size, undifferentiated tumors, increasing depth of submucosal invasion, lymphatic tumor invasion, vascular tumor invasion, increased submucosal vascularity, tumors with a PCNA labeling index of more than 25%, tumors with a gastric mucin phenotype, and vascular endothelial growth factor-C-positive tumors. We identified several variables associated with LN metastasis in EGC. These variables should be included in future research, in order to assess which of these variables remain as significant predictors of LN metastasis.
Gastric Cancer 2008
PMID:Predicting lymph node status in early gastric cancer. 1882 7

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathologic entity causing severe pulmonary hypertension, right-side heart failure, and sudden death. Its histologic features include widespread tumor emboli of the small arteries and arterioles of the lung, associated with thrombus formation and fibrocellular and fibromuscular intimal proliferation. The most frequent causative neoplasm for PTTM is gastric cancer, but lesions in other organs, including the ovary, have been occasionally identified as primary causes. Detailed molecular mechanisms underlying PTTM remain unclear, but some studies have suggested that tissue factor (TF) and vascular endothelial growth factor (VEGF) expressed by tumor cells may be involved in the pathogenesis for cases of gastric cancer. However, little is known about these molecules in PTTM caused by neoplasms of non-gastric origin. Here, we report the autopsy findings of a 42-year-old woman with ovarian cancer showing positive immunoreactivity for both TF and VEGF who died suddenly of PTTM. The present case provides support for the conclusion that these factors may be involved in the pathogenesis of PTTM, independent of the causal neoplasm.
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PMID:Pulmonary tumor thrombotic microangiopathy caused by an ovarian cancer expressing tissue factor and vascular endothelial growth factor. 1883 4

The purpose of this study was to identify genes of interest for a subsequent functional and clinical cohort study using complementary (c)DNA microarrays. cDNA microarray hybridization was performed to identify differentially expressed genes between tumor and nontumor specimens in 30 gastric cancer patients. Subsequent functional studies of the selected gene were carried out, including cell cycle analysis, cell migration analysis, analyses of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF), and oligo-microarray studies using two pairs of stable cell lines of the selected gene. Another independent cohort study of 79 gastric cancer patients was conducted to evaluate the clinical significance of the selected gene in human gastric cancer. Calreticulin (CRT) was selected for further investigation. Two pairs of stable cell lines of CRT overexpression and CRT knockdown were constructed to perform functional studies. CRT enhanced gastric cancer cell proliferation and migration. Overexpressed CRT upregulated the expression and secretion of PlGF and VEGF. CRT had a reciprocal effect on connective tissue growth factor (CTGF) expression. Positive immunohistochemical staining of calreticulin was significantly correlated with high microvessel density (MVD) (p = 0.014), positive serosal invasion (p = 0.013), lymph node metastasis (p = 0.002), perineural invasion (p = 0.008), and poor patient survival (p = 0.0014). Multivariate survival analysis showed that CRT, MVD, and serosal invasion were independent prognosticators. We conclude that CRT overexpression enhances angiogenesis, and facilitates proliferation and migration of gastric cancer cells, which is in line with the association of CRT with MVD, tumor invasion, lymph node metastasis, and survival in gastric cancer patients.
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PMID:Identification of calreticulin as a prognosis marker and angiogenic regulator in human gastric cancer. 1905 Sep 68

Aurora kinase A (AURKA) is located at 20q13, a region that is frequently amplified in gastric cancer. In this study, we have investigated the role of AURKA in regulating glycogen synthase kinase (GSK)-3beta and beta-catenin/TCF complex in gastric cancer cells. Our results demonstrate a significant increase in the phosphorylation of GSK-3beta at Ser 9 following the overexpression of AURKA in AGS cells. The immunoprecipitation with antibodies specific for AURKA and GSK-3beta indicated that the two proteins coexist in the same protein complex. The recombinant human AURKA protein phosphorylated the GSK-3beta protein at Ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (Ser33/37/Thr41) by GSK-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-GSK-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (Ser33/37/Thr41) and accumulation of beta-catenin protein. The knockdown of AURKA reversed the phosphorylation of GSK-3beta and the beta-catenin protein levels. The immunofluorescence analysis demonstrated colocalization of AURKA and GSK-3beta proteins and a significant increase in the nuclear beta-catenin levels in cells overexpressing AURKA. The beta-catenin/TCF transcription activity was measured using the pTopFlash and its mutant pFopFlash luciferase reporter vectors. Indeed, AURKA overexpression led to a significant increase in the pTopFlash reporter activity, whereas kinase dead AURKA mutant (D274A) had no effect. Consistent with these findings, we detected a significant mRNA up-regulation of several direct targets of the beta-catenin/TCF transcription complex (cyclin D1, c-MYC, c-MYC-binding protein, CLDN1, FGF18 and vascular endothelial growth factor), and a two-fold increase in the proliferation rate in AURKA overexpressing cells. We conclude that the AURKA/GSK-3beta interaction is important in regulating beta-catenin, underscoring a novel oncogenic potential for AURKA in gastric tumorigenesis.
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PMID:The aurora kinase A regulates GSK-3beta in gastric cancer cells. 1906 Sep 29

Tumor angiogenesis is a multistep interactive process in which vascular endothelial growth factor (VEGF) and its receptors have a major role. However, the clinical significance of these molecules in gastric cancer (GC) remains unclear. Our study group comprised 86 patients who underwent gastrectomy and subsequently received chemotherapy for recurrent or residual tumor. Using immunohistochemical techniques, we analyzed the expression of VEGF receptors (VEGF-R) 1, 2, and 3. VEGF-R1 expression (defined as >5% staining) was found in the tumor cells of 65 tumors (76%) and in the stromal vessels of 36 tumors (42%). VEGF-R2 expression was found in tumor cells and stromal vessels of 0 and 46 tumors (0 and 53%), respectively, and VEGF-R3 expression was found in tumor cells and stromal vessels of 0 and 75 tumors (0 and 87%), respectively. Univariate analysis revealed that VEGF-R expression correlated with shorter survival (VEGF-R1 in stromal vessels, P = 0.001; VEGF-R2 in stromal vessels, P = 0.009; VEGF-R3 in stromal vessels, P = 0.005) and lower response to S-1 (VEGF-R1 in stromal vessels, P = 0.039). Multivariate analysis of potential prognostic factors showed that VEGF-R1 and VEGF-R2 in stromal vessels were independent predictors of poor outcome. Our data suggest that VEGF-R expression can be a predictor of unfavorable clinical outcome in GC. VEGF-R are promising candidates as therapeutic targets.
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PMID:Impact of vascular endothelial growth factor receptor 1, 2, and 3 expression on the outcome of patients with gastric cancer. 1906 81

This study was aimed to investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 in gastric cancer in order to clarify the role of As2O3 in lymphangiogenesis and metastasis of tumor. The gastric cancer model was established in nude mice by using gastric cancer cell line SGC-7901. As2O3 was injected to the two treatment groups (2.5 mg/kg and 5 mg/kg) and the same volume of saline solution was injected to the control group. Expression of VEGF-C and VEGFR-3 were detected by immunohistochemistry and were analyzed with QWin550cW image Acquiring & Analysis System. The results showed that the expression of VEGF-C and VEGFR-3 in cancer cells significantly reduced in the arsenic -treated groups. The expression of VEGF-C and VEGFR-3 in 5 mg/kg group was significantly less than that in 2.5 mg/kg group. The gray ratio analysis confirmed that there were significant difference between control group and two treated group, as well as between 2.5 mg/kg-treated group and 5 mg/kg-treated group. It is concluded that As2O3 can inhibit expression of VEGF-C and VEGFR-3 of human gastric cancer xenografts in nude mice, which suggests that As2O3 may inhibit the lymphangiogenesis by suppressing the expression of VEGF-C and VEGFR-3.
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PMID:[Effect of arsenic trioxide on vascular endothelial growth factor-C and its receptor (VEGFR-3) in nude mice with gastric cancer]. 1909 32

Regional lymph node metastasis in gastric cancer is a definitive indicator of the patient's prognosis. The goal of this study was to identify the predictors for lymph node metastasis among all the possible histopathological parameters, especially by conducting an objective discrimination of the lymphatic and blood vessels. A total of 210 resected primary gastric cancers with or without lymph node metastasis were evaluated based on the conventional histopathological parameters together with immunohistochemistry using antisera-recognizing lymphatic endothelial hyaluronan receptor-1 (LYVE-1), von Willebrand factor, and lymphangiogenesis promoter vascular endothelial growth factor-C (VEGF-C) antibodies. A multivariate regression analyses of the results indicated that only lymphatic invasion was a significant independent predictor of lymph node metastasis at any stage of cancer invasion. VEGF-C expression was partially related to lymph node metastasis in early gastric cancer. The identification of lymphatic invasion by LYVE-1 antibody is therefore useful to predict regional lymph node metastasis in gastric cancer.
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PMID:Histopathological predictor for regional lymph node metastasis in gastric cancer. 1910 32

A number of advances recently have been made in the chemotherapeutic treatment of gastroesophageal cancer. Perioperative combination chemotherapy based on cisplatin and 5-fluorouracil (5-FU) improves the prognosis of patients with stage II and stage III disease. Preoperative initiation of chemotherapy seems to be essential for achieving this result, according to studies performed in the West. On the other hand, Japanese investigators demonstrated that postoperative administration of oral fluoropyrimidine prodrugs can substantially improve the prognosis of patients with curatively resected gastric cancer. The addition of docetaxel to cisplatin and 5-FU has significantly improved response rate, time to progression, and overall survival in patients treated for advanced gastric cancer, as well as prolonging time to definitive worsening of global health status and Karnofsky performance status. Due to increased hematologic toxicity with this regimen, particularly neutropenic infections, careful patient selection and optimal supportive care, including prophylactic granulocyte colonystimulating factor, are required. Alternative schedules are being investigated that could improve the tolerability of docetaxel plus platinum/fluoropyrimidine combination regimens. Further improvements in outcome may be achieved when even more active chemotherapy combinations including docetaxel are systematically implemented into the preoperative treatment of locally advanced gastroesophageal cancers. Initial results with biologic targeted agents in this setting are promising. Pathways currently under investigation include the epidermal growth factor receptors Her-1 and Her-2, vascular endothelial growth factor, and the epithelial cell adhesion molecule EpCAM. It is hoped that targeting these pathways will further increase the efficacy of biochemotherapy of gastroesophageal cancer. Evaluating early response to biochemotherapy using metabolic imaging is a novel approach that may allow for tailoring systemic therapy to individual tumor biology. A deeper understanding of the relevant pathognomonic molecular patterns and signatures in individual tumors may facilitate faster drug development and permit more accurate selection of active therapies in the future.
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PMID:Current status and future of chemotherapy and biochemotherapy in gastroesophageal cancers. 1996 33

IL-18 has recently been reported to play a critical role in tumor migration, invasion, and metastasis. Because IL-18 has various biological activities after its secretion as an 18 kDa mature form, the regulation of the IL-18 secretion process is an important step in tumor progression. This study investigated the implication of IL-18 in vascular endothelial growth factor (VEGF)-D-regulated migration, along with the role of the IL-18 secretion process. VEGF-D enhanced cell migration, which was then blocked by inhibiting IL-18. VEGF-D increased IL-18 expression and secretion, suggesting that IL-18 is a critical mediator for VEGF-D-enhanced migration. VEGF-D induced a disintegrin and metalloprotease 33 (ADAM33) expression, which has a metalloproteinase domain. VEGF-D-enhanced IL-18 secretion and cell migration were inhibited by ADAM33 knock-down. Moreover, cell proliferation was considerably reduced in ADAM33 small interfering RNA transfectants. In conclusion, ADAM33 has a key role in gastric cancer pathogenesis by up-regulating IL-18 secretion process, resulting in increased cell migration and proliferation.
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PMID:Expression of ADAM33 is a novel regulatory mechanism in IL-18-secreted process in gastric cancer. 1926 33


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