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

Genetic changes leading to protooncogene activation qualitatively and/or quantitatively alter their gene products and are exclusively or largely restricted to transforming cells and their precursors. The overexpression of HER2 is among those changes and is often detected in adenocarcinomas such as breast, ovarian, lung, and gastric cancer. This provides a rationale for exploring the possibility that HER2 is a target of host immune responses against cancer cells. We have recently demonstrated that HER2 can be a target for tumor-rejecting immune responses against syngeneic murine HER2+ tumor cells. We defined two different peptides, HER2p63-71 and HER2p780-788, with a Kd anchor motif that can induce CD8+ cytotoxic T lymphocytes (CTLs). The growth of HER2+ syngeneic tumors was suppressed in mice immunized with HER2p63-71 or p780-788. Since murine Kd and human HLA-A24 share a similar anchor motif for peptides, HER2p63 71 and HER2p780-788 were examined for induction of CTLs in HLA-A24+ individuals. CD8+ CTL clones specific for these peptides were established and they lysed HER2+ tumor cells in a human leukocyte antigen (HLA)-A24-restricted manner. To elicit specific CD8+ T cell immune responses against cancer, the development of efficient devices to deliver tumor antigen peptides to the major histocompatibility complex (MHC) class I pathway constitutes a central issue. We have developed a novel formula of hydrophobized polysaccharide nanoparticles which can deliver a HER2 oncoprotein containing an epitope peptide to the MHC class I pathway. We designed a simple protein delivery system: cholesteryl group-bearing polysaccharides, mannan or pullulan (CHM or CHP, respectively), complexed with the truncated HER2 protein containing the 147 N-terminal amino acids. These complexes were able to induce CD8+ CTLs against HER2+ tumors. CTLs were MHC class I restricted and specifically recognized HER2p63-71, a part of a truncated HER2 protein used as an immunogen. The complete rejection of tumors also occurred when CHM-HER2 was applied early after tumor implantation. In the effector phase of in vivo tumor rejection, CD8+ T cells played a major role. The results suggest that this unique hydrophobized polysaccharide may help soluble proteins to induce cellular immunity. Such a novel vaccine may be of potential benefit in cancer prevention and cancer therapy.
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PMID:Development of a cancer vaccine: peptides, proteins, and DNA. 1095 Jan 53

Our previous comparative genomic hybridization (CGH) study revealed a novel amplified region at 15q26 in two cell lines established from diffuse types of gastric cancer (GC). In this amplified region, FES and IGF1R, known targets on 15q26, were located telomeric to the amplicon in the two cell lines, HSC39 and 40A, suggesting that another tumor-associated gene exists in this region. While screening expressed sequence tags (ESTs) for novel genes in this region, we identified the IQGAP1 amplification. IQGAP1 has been reported to encode a ras GAP-related protein, and its interaction with cadherin and/or beta-catenin induces a dissociation of beta-catenin from the cadherin-catenin complex, one of the mechanisms for cell-cell adhesion. Northern and Western blot analyses revealed that amplification of this gene was accompanied by corresponding increases in mRNA and protein expression. Moreover, immunocytochemical staining showed that overexpressed IQGAP1 accumulated at the membrane, suggesting its colocalization with beta-catenin. Taken together, these findings suggest that IQGAP1 may be one of the target genes in the 15q26 amplicon correlated with a malignant phenotype of gastric cancer cells, such as diffuse and invasive characteristics, through the disruption of E-cadherin-mediated cell-cell adhesion.
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PMID:IQGAP1, a negative regulator of cell-cell adhesion, is upregulated by gene amplification at 15q26 in gastric cancer cell lines HSC39 and 40A. 1128 14

Autosomal dominant disorders of skeletal and cranial development have been linked to fibroblast growth factor receptor (FGFR) 2 and FGFR3. Here we report two identical mutations in FGFR2 that cause craniosynostosis syndromes, Crouzon, Apert, and Pfeiffer in gastric carcinoma. A missense mutation (Ser267Pro) in exon IIIa and a splice site mutation (940-2A-->G) in exon IIIc were detected in gastric cancer patients. Interestingly, these heterozygous somatic mutations are identical to the germinal activating mutations in FGFR2 reported previously in craniosynostosis syndromes. In addition, the two novel mutations of FGFR3 in colorectal carcinomas were identified. All identified mutations occurred at highly conserved sequences, not only in the FGFR family of molecules, but also throughout evolution and clustered in the immunoglobulin-like loop-III domain, highlighting the functional importance of this domain. Our results indicate that FGFR2 and FGFR3, in addition to their potential role in skeletal dysplasias, play an important role in tumorigenesis.
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PMID:Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. 1132 14

Overexpression of the HER2 (neu/c-erbB-2) oncogene frequently coincides with an aggressive clinical course of certain human adenocarcinomas. Expression and secretion of aberrant HER2 splice variants has been reported in various cell lines and tissues and can interfere with the oncogenic HER2 activity. Here we demonstrate, using two different approaches, that expression of a truncated 100 kDa HER2 variant which encodes the extracellular domain of HER2 (HER-ECD) inhibits growth factor-mediated tumour cell proliferation. A HER2-ECD cDNA encoding the truncated variant was overexpressed in MCF7 breast cancer cells. HER2-ECD overexpression decreased spontaneous proliferation of MCF7 cells as well as heregulin-mediated soft agar colony formation. Concomitantly, heregulin-induced phosphorylation of HER4 as well as downstream activation of p44/p42 MAP-kinases was decreased. To confirm these data, ribozymes were targeted to the 3'-untranslated region of the 2.3 kb HER2-ECD mRNA which is spontaneously expressed in MKN7 gastric cancer cells. HER2-ECD-targeted ribozymes downregulated HER2-ECD expression and enhanced EGF-mediated soft agar colony formation of MKN7 cells. In parallel, EGF-induced activation of p44/p42 MAP-kinases and activation of c-Fos expression were increased in ribozyme-transfected MKN7 cells. Finally, in RT-PCR we found a trend towards a progressive loss of 2.3 kb HER2-ECD mRNA expression in more advanced gastric tumours. These data show that the HER2-ECD variant inhibits growth factor-mediated tumour cell proliferation suggesting an important role during the progression of human cancer.
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PMID:Expression of a truncated 100 kDa HER2 splice variant acts as an endogenous inhibitor of tumour cell proliferation. 1136 Jan 94

The efficacy of a phosphorothioate antisense oligonucleotide (ASO) for KDR/Flk-1 (KDR/Flk-1-ASO), an endothelial cell-specific vascular endothelial growth factor (VEGF) receptor, was investigated on the peritoneal dissemination and angiogenesis of a human gastric cancer cell line in nude mice. Green fluorescent protein (GFP)-transduced NUGC-4 (NUGC-4-GFP) human gastric cancer cells were implanted into the peritoneal cavity of nude mice. KDR/Flk-1-ASO, -SO, or phosphate-buffered saline was administrated from days 7 to 14, 200 microg/mouse, once a day. The mice were sacrificed on day 28. Disseminated peritoneal tumor nodules expressing GFP were visualized by fluorescence microscopy. KDR/Flk-1-ASO significantly decreased the extent of peritoneal dissemination of the tumors. The number of cells undergoing apoptosis was significantly increased in the KDR/Flk-1-ASO-treated tumors. Microvessel density was significantly reduced in the KDR/Flk-1-ASO-treated tumor nodules. The KDR/Flk-1 antisense strategy, therefore, decreases tumor dissemination apparently by inhibiting angiogenesis.
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PMID:VEGF receptor antisense therapy inhibits angiogenesis and peritoneal dissemination of human gastric cancer in nude mice. 1185 38

DNA copy number gains and amplifications at 17q are frequent in gastriccancer, yet systematic analyses of the 17q amplicon have not been performed. In this study, we carried out a comprehensive analysis of copy number and expression levels of 636 chromosome 17-specific genes in gastric cancer by using a custom-made chromosome 17-specific cDNA microarray. Analysis of DNA copy number changes by comparative genomic hybridization on cDNA microarray revealed increased copy numbers of 11 known genes (ERBB2, TOP2A, GRB7, ACLY, PIP5K2B, MPRL45, MKP-L, LHX1, MLN51, MLN64, and RPL27) and seven expressed sequence tags (ESTs) that mapped to 17q12-q21 region. To investigate the genes transcribed at the 17q, we performed gene expression analyses on an identical cDNA microarray. Our expression analysis showed overexpression of 8 genes (ERBB2, TOP2A, GRB2, AOC3, AP2B1, KRT14, JUP, and ITGA3) and two ESTs. Of the commonly amplified transcripts, an uncharacterized EST AA552509 and the TOP2A gene were most frequently overexpressed in 82% of the samples. Additional studies will be initiated to understand the possible biological and clinical significance of these genes in gastric cancer development and progression.
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PMID:Targets of gene amplification and overexpression at 17q in gastric cancer. 1198 Jun 59

Thymidine kinase 1 in serum (STK1) of patients with gastric cancer was determined by two methods: ECL dot blot and radioactivity assay. Both measurements showed significantly different values for preoperative STK1 and healthy STK1 (p=0.012 for ECL dot blot and p=0.003 for the radioactivity assay). The preliminary results of ECL dot blot STK1 measurement showed that in tumor-free subjects the level of the enzyme was significantly reduced to 52.7% 35 days after surgery (n=8, p=0.0106). The decrease in STK1 levels in the tumor-free subjects paralleled the decline of the half-life of the STK1 enzyme. In patients with distant metastases (n=6) the enzyme level had increased to 173% 35 days postoperatively. By contrast, with the radioactivity assay no significant differences in thymidine kinase activity for 0-day-postoperative patients and 35-day-postoperative tumor-free patients was found (p=0.329). The activity decreased to 80% in 35-day-postoperative patients with metastatic disease. We suggest that the value of the half-life of STK1 measured by ECL dot blot can be used as a potential marker for monitoring the response to surgery in patients with gastric or other cancers one month after surgery.
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PMID:The half-life of thymidine kinase 1 in serum measured by ECL dot blot: a potential marker for monitoring the response to surgery of patients with gastric cancer. 1211 81

Differentiation-inducing factor-1 (DIF-1) is a chlorinated hexaphenone isolated from Dictyostelium. DIF-1 exhibits antitumor activity in several types of mammalian tumor cells, although the underlying mechanisms remain unknown. On the other hand, recent studies indicate that constitutively activated STAT3 acts as an oncogene and could be a target for antitumor drug. In the present study, we examined the effects of DIF-1 on proliferation of gastric cancer cell lines as well as on its signal transduction pathways, focusing mainly on STAT proteins. DIF-1 inhibited proliferation of gastric cancer cells. Western blot analysis and electrophoretic mobility shift assay showed that DIF-1 inhibited STAT3 activity in an MEK-ERK-dependent manner in gastric cancer cell lines, AGS and MKN28. Moreover, blockade of STAT3 activity by ectopic expression of dominant-negative STAT3 or the Janus kinase inhibitor, tyrphostin AG490, inhibited cell growth of AGS cells. These results suggest that STAT3 activity plays an important role for cell growth in AGS cells, and raises the possibility that inhibition of STAT3 activity is one of the mechanisms responsible for the antitumor effect of DIF-1 in these cells.
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PMID:Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway. 1255 68

Common fragile sites predispose to specific chromosomal breakage associated with deletion, amplification, and/or translocation in certain forms of cancer. Chromosomal fragile sites not only are susceptible to DNA instability in cancer cells, but may also be associated with genes that contribute to the neoplastic process. FRA7G is a common fragile site containing the candidate tumor suppressor genes CAV1, CAV2, and TESTIN (TES). The human gastric cancer cell line GTL-16 has an amplification of this genomic region and was used to seek evidence for the suppressor candidacy of one of these genes. Our results demonstrate that CAV1, CAV2, and TESTIN are coamplified with the MET oncogene and overexpressed in GTL-16. Somatic mutation was not detected in the coding regions of these genes, although they were each overexpressed. The results show that CAV1, CAV2, and TESTIN are not tumor suppressor genes in this gastric cancer.
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PMID:Candidate tumor suppressor genes at FRA7G are coamplified with MET and do not suppress malignancy in a gastric cancer. 1262 Mar 87

The origin, characteristics, and lifetime risk for the following five types of hereditary cancer (HCS) syndromes are briefly described in this review: hereditary breast and ovarian cancer (HBOC) syndrome, familial adenomatous polyposis (FAP), and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, hereditary diffuse gastric cancer (HDGC) syndrome, and medullary thyroid carcinoma (MTC). Most are caused by mutations in tumor suppressor genes. In HCS, a single copy of the mutated tumor suppressor gene is inherited, and mutation of the second wild type allele of the gene is required for tumorigenesis. Patients with HCS have a higher than normal risk of a second malignancy. Management strategies to address increased cancer risk in HCS include genetic counseling and testing, targeted surveillance, chemoprevention, and prophylactic surgery. Genetic testing for high-risk family members is strongly recommended. Available data indicate surgical prophylaxis is more successful than surveillance in reducing cancer risk in carriers of BRCA, CDH1, APC, and RET mutation.
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PMID:Molecular genetics and management strategies in hereditary cancer syndromes. 1267 1


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