UMLS:C0024623 - FACTA Search

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Query: UMLS:C0024623 (gastric cancer)
36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since gastric cancer is an exceptional heterogeneous tumor conflicting results have been obtained about the relationship between genotype and phenotype. From the molecular point of view gastric carcinoma diffuse type forms a distinct entity which is microsatellite stable, has almost no p53 mutations and exhibits in at least half of the cases mutations in the E-cadherin gene. In contrast, all other gastric carcinomas comprise a heterogeneous group of which about one third exhibits microsatellite instability (MSI) but no p53 protein stabilization or gene mutations. These tumors are either of pure intestinal (glandular) type or show large solid (medullary) tumor cell clusters. Thereby, in sporadic gastric cancer MSI is caused by loss of hMLH1 expression due to hypermethylation of the promotor region rather than by mutation of the gene itself. Tumors that are microsatellite stable (MSS) and show p53 alterations are either intestinal (about 70%) or a mixed-type encompassing at least 5% glandular and poorly differentiated diffuse components (about 30%). Whereas pure diffuse type gastric cancer is unlikely to develop from intestinal type carcinoma, this may, however, be the case in some advanced mixed-type gastric cancers.
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PMID:[Correlation between histological and molecular mechanisms of carcinogenesis in stomach cancer]. 1071 97

E-cadherin is a homophilic cell adhesion molecule that is mutated in half of diffuse-type gastric cancer patients. Since these mutations generally affect the extracellular portion of the transmembrane molecule and do not interrupt the reading frame, altered E-cadherin protein may be an excellent tumor marker. We established a rapid PCR-based E-cadherin mutation detection technique allowing positive results within a day. Furthermore, we succeeded in the generation of monoclonal antibodies that specifically react with mutant E-cadherin but not with the wild-type protein. In gastric carcinoma specimens known to express mutant E-cadherin messenger RNA these monoclonal antibodies target exclusively tumor cells in routine formalin fixed and paraffin embedded material from biopsies, primary tumors and lymph node metastases. Non-tumorous cells, including normal gastric epithelium expressing wild-type E-cadherin, are not stained. The unique type of E-cadherin mutations in diffuse-type gastric cancer (missense mutations and complete or partial in-frame deletions of exons) might improve the information of conventional diagnostic techniques. In addition, they may open novel and more selective clinical avenues to treat small tumor deposits for adjuvant-, neoadjuvant- and additive-therapy.
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PMID:[Diffuse stomach carcinoma: from H&E diagnosis and molecular pathology to specific therapy]. 1071 5

Somatic deletion mutations in the cell adhesion molecule E-cadherin are present in almost 50% of diffuse type gastric cancer. We recently generated monoclonal antibodies against an in-frame deletion of exon 9. The aim of this study was to generate and characterize monoclonal antibodies against the second mutational hot spot, in-frame deletions of exon 8. Lou/C rats were immunized using a KLH-coupled peptide that represents a unique sequence generated by fusion of exon 7 and exon 9 from an E-cadherin deletion mutation lacking exon 8. Hybridoma supernatants were tested in a solid-phase immunoassay using BSA-coupled peptide. Positive reacting hybridomas were confirmed by Western Blots, FACS analysis, and immunohistochemistry of E-cadherin negative carcinoma cells that had been transfected with mutant and wild-type E-cadherin cDNA, respectively. In addition, routine formalin fixed and paraffin embedded tissues from gastric cancer patients were analyzed using both mutation-specific and commercial monoclonal antibodies against E-cadherin, including HECD-1 and AEC. Two hybridoma supernatants, termed E-cad delta 8-1, were selected that reacted with the mutant peptide used for immunization and gave strong signals in Western Blot and FACS analysis with cells expressing mutant E-cadherin lacking exon 8. Wild-type protein expressing cells only reacted with the commercial antibodies but not with the two selected hybridoma supernatants. In contrast to AEC, monoclonal antibody HECD-1 did not react with exon 8 deleted E-cadherin, suggesting that the previously unknown epitope for this often used monoclonal antibody is located at least in part within exon 8. Four gastric cancer specimens known to express mutated E-cadherin mRNA strongly reacted with both mutation-specific supernatants and with AEC monoclonal antibody but not with HECD-1. Taken together, we succeeded in generating monoclonal antibodies reacting with mutant E-cadherin protein lacking exon 8. Furthermore, using both HECD-1 and the new mutation-specific antibodies E-cadherin immunoreactivity can for the first time be evaluated in an allele-specific manner in archival tissues.
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PMID:[Novel mutation-specific monoclonal E-cadherin antibodies make possible allele differentiation at the protein level in tumors]. 1071 16

Despite a dramatic reduction in incidence and mortality rates, gastric cancer (GC) is still one of the most common malignant neoplasias worldwide. Surgical and medical treatments have not substantially improved during the last decades, and large-scale early diagnosis programs have proven feasible in only one high-risk country, Japan. A large number of studies have indicated that salted, smoked, pickled, and preserved foods (rich in salt, nitrite, and preformed N-nitroso compounds) are associated with an increased risk of GC. In contrast, strong evidence has been provided that high consumption of fresh fruit and raw vegetables and a high intake of antioxidants are associated with a reduced risk of GC. Domestic refrigeration and reduced salt consumption are considered to play a role in explaining the decreasing temporal trend and the geographical patterns of GC. Familial factors have been suspected to play a role in GC susceptibility, and recently germ line mutations in the E-cadherin gene were identified in a few families. Evidence of a positive association between Helicobacter pylori infection and GC risk has been provided by most prospective studies that overall suggest a two- to threefold increase in risk. Randomized intervention studies on H. pylori eradication and its effects on GC predisposing conditions (atrophic gastritis and intestinal metaplasia) are in progress and represent a priority for epidemiological research in view of the potential preventive applications. Overall, it is evident that several factors (including diet, individual susceptibility and H. pylori infection) interact in a complex multifactorial process, leading over a long period of time to GC.
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PMID:Epidemiology of gastric cancer: an evaluation of available evidence. 1077 25

The actual mechanisms by which carcinoma cells metastasize to lymph nodes are still unclear, and there is a need to establish in vivo experimental models suitable for the investigation of lymph node metastasis. For the purpose, we established a highly lymph node-metastasizing line, designated AZL5G, derived from a human gastric cancer cell line, AZ521, which had low capacity for lymph node metastasis. AZL5G cells transplanted orthotopically in the nude mouse stomach metastasize predominantly to the regional lymph nodes, showing little potential for hematogenous metastasis. AZL5G tumors developing in the stomach and regional lymph nodes showed poorly differentiated adenocarcinoma with medullary growth, and their histologic appearance strongly resembled that of parental AZ521. The growth activities in vitro of low-metastatic AZ521 and high-metastatic AZL5G were almost the same, but the tumorigenicity in vivo of AZL5G was significantly higher than that of AZ521. AZL5G cells also showed clearly higher abilities of cell locomotion and adhesion to type IV collagen and fibronectin in vitro as compared with AZ521 cells. Flow cytometric analysis demonstrated that the expression of integrin beta1 subfamily except for alpha6 integrin was generally increased in AZL5G cells than in AZ521 cells. Especially, the expression of alpha1 and alpha2 integrins in AZL5G cells was clearly higher than in AZ521, while alpha(v)beta3 integrin, E-cadherin, ICAM-1 and CD44H were not expressed by either cell line. The cell adhesion blocking assay showed that DGEA-containing peptide, which is composed of alpha2 integrin recognition sequence, significantly reduced the adhesiveness of AZL5G cells to type IV collagen as well as to type I collagen and laminin. Furthermore, the administration of anti-alpha2 integrin mAb or DGEA peptide in AZL5G-transplanted nude mice produced a significant reduction in the number of lymph node metastases. These data suggest that the up-regulation of alpha2 integrin expression by gastric cancer cells may play a critical role in the process of lymph node metastasis through the increased adhesiveness to type IV collagen. In conclusion, we established a gastric cancer cell line, AZL5G, with a highly metastatic potential to lymph nodes. This well-characterized line and its in vivo experimental model should be useful for investigation of the mechanisms of lymph node metastasis and for establishment of a new therapeutic approach for human gastric cancer.
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PMID:Establishment and characterization of a human gastric carcinoma cell line that is highly metastatic to lymph nodes. 1084 Sep 45

The expression of interleukin 8 (IL-8) by human gastric carcinomas directly correlates with tumor vascularity and disease progression. To determine whether IL-8 can act in an autocrine manner to regulate the expression of other disease-progression genes, we examined the expression of IL-8 receptors IL-8RA (CXCR1) and IL-8RB (CXCR2) in six different human gastric carcinoma cell lines and 38 surgical specimens of human gastric carcinomas. All of the gastric carcinoma cell lines expressed mRNA and protein for IL-8RA and IL-8RB protein. In all surgical specimens, the majority of the tumor cells and small vessel endothelial cells stained positive for IL-8RA and IL-8RB protein. In vitro treatment of human gastric cancer MKN-1 cells with exogenous IL-8 enhanced the expression of epidermal growth factor receptor, type IV collagenase (metalloproteinase-9), vascular endothelial growth factor, and IL-8 mRNA. In contrast, treatment with exogenous IL-8 decreased expression of E-cadherin mRNA. IL-8 treatment increased invasive capacity of MKN-1 cells, which was associated with activity of metalloproteinase-9. Collectively, these results demonstrate that human gastric carcinoma cells express receptors for IL-8 and that IL-8 may play a role in the progressive growth of human gastric carcinoma by autocrine/paracrine mechanisms.
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PMID:Regulation of disease-progression genes in human gastric carcinoma cells by interleukin 8. 1091 18

Literature on familial gastric cancer was reviewed from the stand point of genetic and clinico-pathological aspects. Germline mutations of the E-cadherin gene were found in about one quarter of diffuse type cases of familial gastric cancer in kindreds of New Zealand and Europe, while the E-cadherin gene may not be responsible for most Japanese familial gastric cancer cases. It is likely that mismatch repair genes are not major causative genes for familial gastric cancer. Additional studies are necessary to elucidate the nature of familial gastric cancer including that of intestinal type. Prophylactic gastrectomy is effective in preventing gastric carcinoma, but it is not generally recommended at present for all E-cadherin mutation carriers in Japan.
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PMID:[Familial gastric cancer]. 1092 36

Stomach cancer is the major malignancy in Japan and one of the most common cancers worldwide. To establish the basis for an immunotherapeutic approach to stomach cancer, we have initiated an analysis of stomach cancer antigens recognized by human immunoglobulin G (IgG) antibodies using SE-REX, a powerful expression cloning method developed by Dr. M. Pfreundschuh's group. Five stomach cancer cDNA libraries have been screened with autologous patient sera: one moderately differentiated adenocarcinoma; two poorly differentiated adenocarcinomas; and two scirrhous-type poorly differentiated adenocarcinomas of Borrmann type 4, the most devastating form of stomach cancer. Based on the reactivities of clones with autologous IgG antibodies, an average of 50 independent clones from each library and a total of 297 clones were isolated. DNA sequencing revealed that these 297 clones were derived from 136 different genes. Comparison of the 136 genes to sequences in DNA databases showed that 95 are previously identified genes and 41 are newly identified in this study. The antigens are derived from various genes including a chimeric gene between E-cadherin and an unknown gene Y, AKT oncogene, genes overexpressed in stomach cancers, genes of which the transcripts are alternatively or aberrantly spliced, and genes known to be involved in autoimmune diseases. Thus stomach cancer patients can generate an immune response against a surprisingly diverse set of gene products. To identify antigens potentially useful in the diagnosis and therapy of gastric cancer, all 136 genes were tested for their reactivities with a panel of sera from 44 gastric cancer patients (17 women and 27 men, aged 35-81 years) and with a panel of sera from 100 control individuals with no previous history of cancer but some of whom had gastritis (55 women and 45 men, aged 30-69 years). Eleven antigens showed reactivity only with a certain proportion of cancer patient sera but not with any control sera. An additional 12 antigens elicited antibody production at a much higher frequency in cancer patients than in control individuals. To evaluate the clinical usefulness of these antigens we are now examining their expression in normal and malignant tissues.
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PMID:SEREX analysis of gastric cancer antigens. 1095 Jan 46

Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.
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PMID:Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. 1097 39

S100A4 is known to be involved in cancer cell motility by virtue of its ability to activate nonmuscle myosin. E-cadherin has an important role in the homophilic cell-cell adhesion and is called an invasion suppressor gene. In the current study, we investigate the histological type and metastatic potential of gastric cancer from the aspect of the interrelationship of E-cadherin and S100A4 expression. Expression of E-cadherin and S100A4 in gastric cancer cell lines, primary gastric cancers, and their normal counterparts were analyzed by reverse transcription-PCR, Western blot, and immunohistochemical methods. S100A4 protein and E-cadherin were expressed in five of eight gastric cancer cell lines, and inverse expression of the two proteins are found in four cell lines. In the clinical specimens, E-cadherin mRNA expression in differentiated adenocarcinomas (88%, 14 of 16) was significantly more frequent than that in poorly differentiated adenocarcinomas (50%, 22 of 44; P = 0.015). Western blot analysis demonstrates that S100A4 protein expression in poorly differentiated adenocarcinomas was 1.6-fold higher than in well differentiated adenocarcinoma. Immunohistochemically, S100A4 expression was detected in 51 (55%) of 92 primary gastric cancers. Reduced expression of E-cadherin in primary tumors was found in 66 (72%) of 92 tumors. S100A4 expression in the poorly differentiated adenocarcinomas had a strong relation to positive lymph node involvement or peritoneal dissemination. Reduced E-cadherin expression showed a strong relationship with positive serosal involvement and infiltrating type. Tumors classified as a group with reduced E-cadherin and high expression of S100A4 reveal positive peritoneal dissemination, serosal involvement, and infiltrating type in the growth pattern. Furthermore, these tumors showed a strong correlation with the poorly differentiated adenocarcinoma. In contrast, tumors with preserved E-cadherin and low expression of S100A4 have a close relation to the well differentiated adenocarcinoma and a favorable prognosis. By the Cox proportional hazard model, S100A4 and E-cadherin tissue status was judged as an independent prognostic factor. S100A4 and E-cadherin tissue status may be a powerful aid in evaluating metastatic potential or the prognosis of patients with gastric cancer.
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PMID:Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer. 1110 37

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