Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of cyclooxygenase-2 (COX-2) has been reported in gastric cancers. However, the relationship between expression of COX-2 and clinico-pathological or genotypic features has not been elucidated. To address the issue, expression of COX-2 protein was analyzed in 100 gastric cancers as well as 7 gastric cancer cell lines by using immunoblot analysis. Overexpression of COX-2 in cancer tissues compared with matched non-cancerous tissues was found in 70% of cases and was significantly associated with lymphatic involvement, lymph node metastasis and advanced tumor stage. Interestingly, overexpression of COX-2 was less frequent in gastric cancers with microsatellite instability (MSI) than in those without MSI (8/20 vs. 62/80, p < 0.01). Expression of COX-2 protein was detected in some gastric cancer cell lines without MSI at various levels, but not in those with MSI. Our results suggest that overexpression of COX-2 may play an important role in tumor progression of gastric cancer and also support the notion that gastric cancers with and without MSI represent distinctive pathways of carcinogenesis. We also observed a reduction of MSI phenotype after aspirin or sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which lacks COX-2 expression. Int. J. Cancer (Pred. Oncol.) 84:400-403, 1999.
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PMID:Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellite instability. 1040 93

Protein tyrosine kinases (PTKs) are a major class of proto-oncogenes that are involved in tumor progression. The purpose of this study was to establish a comprehensive PTK expression profile in gastric cancers, with the objective of identifying possible biomarkers for gastric cancer progression. We have designed degenerate primers according to the consensus catalytic motifs to amplify PTK molecules from gastric cancers by reverse transcriptase-PCR methods. The PTK expression profile was established by sequencing analysis of the cloned PCR products. We have identified 17 PTKs from a gastric adenocarcinoma. Two receptor PTKs, tie-1 and axl, were selected for in situ immunohistochemistry studies because of their higher expression level and their described roles in adhesion, invasion, and angiogenesis. Among the 97 gastric adenocarcinoma tissues examined, we observed positive immunohistochemical staining of tie-1 PTK in 69 and positive staining of axl kinase in 71 tissues. Statistical analysis with clinicopathological features indicates that tie-1 kinase expression is inversely correlated with patients' survival, whereas axl fails to show similar clinical significance. Our results illustrate the utility of tyrosine kinase gene family profiling in human gastric cancers and show that tie-1 tyrosine kinase may serve as a novel independent prognostic marker for gastric adenocarcinoma patients.
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PMID:tie-1 protein tyrosine kinase: a novel independent prognostic marker for gastric cancer. 1043 78

Tumor progression is associated with the clonal expansion of surviving cell variants. These results in cancer cell heterogeneity and selection of cells with a high malignant potential reflected also by the ability to metastasize. In seeding and implantation of cancer cells at the distant site cell adhesion molecules play a crucial role. Of particular interest is CD44 adhesion molecule, which possibly is involved in tumor metastasis development. Forty cases of an advanced gastric cancer were studied. Paraffin block were collected from the files. In addition to routine tumor typing, grading (Lauren and Goseki classifications) and staging, CD44 (standard, v5 and v6) was studied by immunohistochemistry and RT-PCR. CD44 immunoreactivity was found in 36 of the 40 studied cases. A significant overexpression of CD44v5 was noticed in gastric cancer. This was especially seen in Goseki's grades I and III (72.7% of cases) and was less common in Goseki's grades II and IV (44.4% of cases). CD44v6 was less commonly expressed. In some cases CD44 heterogeneity of neoplastic intravascular emboli was noticed and in some other cases stronger expression of CD44 was present in deeper parts of cancer infiltrate. Immunohistochemical expression was mostly in concert with CD44 gene expression as shown by RT-PCR results. Some discrepancies are discussed. These findings are interesting in view of better prognosis and different route of dissemination of Goseki's grades I + III compared with Goseki's grades II + IV of the gastric cancer. We have shown an overexpression of CD44v5 in an advanced gastric cancer, especially in Goseki's grades I and III. This could reflect a different malignant potential and a different route of dissemination of gastric well differentiated adenocarcinomas.
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PMID:Preferential overexpression of CD44v5 in advanced gastric carcinoma Goseki grades I and III. 1062 17

G1 cyclins and cyclin-dependent kinase (CDK) complexes play important roles in G1 cell cycle transition, and their overexpression is implicated for neoplasia. The p27 protein (p27) negatively regulates G1 progression by binding to G1 cyclins/CDK complexes and inhibits their activity, resulting in inhibition of entry to the cell cycle. We investigated overexpression of cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin E (CCNE), CDK2, and CDK4, in addition to p27, in 260 gastric cancer cases on the basis of Western blots, reverse transcriptase-polymerase chain reaction Southern blots, and immunohistochemistry to clarify the roles of these proteins in tumor progression and prognosis. Examination of 20 cases of fresh cancer and matched normal tissues demonstrated a clear tendency for increased mRNA synthesis to be more frequent than expected from protein levels, and a direct correlation between p27 protein and mRNA was not found. Immunohistochemistry demonstrated 21. 5%, 34.2%, 30.4%, 44.2%, and 48.0% positivity for CCND1, CCND2, CCNE, CDK2, and CDK4, respectively, in the 260 gastric cancer cases. Overexpression of CCND2 and CDK4 significantly correlated with tumor progression. Moreover, CCND2 cytoplasmic staining (26.2%) appeared to be strictly linked with progression, whereas nuclear staining (7. 8%) demonstrated an inverse correlation. Survival curves showed CCND2 (especially cytoplasmic staining) and CDK4 positivity to be associated with a poor prognosis and CCNE positivity with a better prognosis. Tumors with high p27 labeling indices (LIs) were well differentiated, with low levels of invasion and lymph node metastasis. p27-negative cases (37.3%) demonstrated a poor prognosis. Multivariate analysis revealed positivity for CCND2 and negativity for p27 to be independent prognostic factors. There were no direct links among CCND2, CCNE, CDK4, and p27. The results indicate that CCND2 cytoplasmic localization might reflect an important physiological role in tumor progression, whereas CCNE overexpression correlates with differentiation and a good prognosis, possibly because of accumulation of inactive forms of CCNE-CDK2 complexes. Loss of p27 caused by degradation activity may affect tumor cell growth in the presence of an altered extracellular matrix, facilitating metastasis. Cell-cycle-regulatory proteins appear to work independently.
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PMID:Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. 1066 88

Liver cancer and gastric cancer are the most common solid tumors worldwide. Transforming growth factor-beta (TGF-beta) production and lack of response to TGF-beta growth inhibitory effects have been associated with tumor progression and therapeutic resistance. HepG2, Hep3B, and SK-HEP-1 human liver cancer lines produce 3, 5.7, and 2.5 ng TGF-beta1; 1.4, 2, and 4 ng TGF-beta2 and 0.15, 0.2 and 0.22 ng TGF-beta3 per 107 cells (24 h). Expression of the TGF-beta type I receptor is 20x, 1x, and 0.6x the level in mink lung MvLu1 cells in the HepG2, Hep3B, and SK-HEP-1 cells, respectively. HepG2 and Hep3B cells do not express the TGF-beta type II receptor while SK-HEP-1 cells express 7x the level found in mink lung MvLu1 cells. Hs 746T, KATO III, RF-1, and RF-48 human gastric cancer cell lines produce 12. 5, 0.35, 0.4, and 0.4 ng TGF-beta1; 2.6, 0.95, 0.5, and 0.52 ng TGF-beta2 and 0.42, 0.17, 0.12, and 0.14 ng TGF-beta3 per 107 cells (24 h). Expression of TGF-beta type I receptor is 0.7x, 0.7x, 0.8x, 0.6x the level in mink lung MvLu1 cells in the Hs 746T, KATO III, RF-1 and RF-48 cells, respectively. KATO III cells are lacking in the TGF-beta type II receptor while Hs 746T, RF-1 and RF-48 cells express 10x, 0.8x, and 1x the levels in mink lung MvLu1 cells. The IC50 for TGF-beta1 is >>10 ng/ml in all of these lines except RF-48 where TGF-beta1 is mitogenic. The response of the cell lines to radiation, doxorubicin, mitomycin C, cisplatin, 5-fluorouracil, methotrexate, and gemcitabine showed that SK-HEP-1 was the most drug resistant liver cancer cell line and KATO III was the most drug resistant gastric cancer cell line. Overall, there was no correlation between TGF-beta secretion in cell culture and sensitivity of the cells to anticancer agents. Increased TGF-beta1 levels were detectable in the plasma of nude mice bearing Hep3B and Hs 746T xenografts. Those tumors which secreted greater amounts of TGF-beta were more therapeutically resistant in vivo.
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PMID:Transforming growth factor-beta and response to anticancer therapies in human liver and gastric tumors in vitro and in vivo. 1067 95

The loss of mismatch repair enzymes increases the mutation rate in microsatellites and coding regions of the genome and appears to be involved in drug resistance. The replication error (RER+) phenotype, associated with microsatellite instability, has been widely described for both familial and sporadic colon cancers and for gastric and endometrial tumors. For ovarian cancer, the incidence of RER+ cases among sporadic tumors is still uncertain. We analyzed epithelial ovarian tumors and ovarian carcinoma cell lines for microsatellite instability and for mutations in the coding regions of different genes, including the recently discovered human CHK-1 gene, which has an important role in controlling cell cycle progression and whose coding region contains a poly(A)9 tract. Microsatellite instability and frameshift mutations in coding regions of BAX, TGFbetaRII, IGFIIR, E2F-4, ICE, and CHK-1 genes were analyzed in ovarian cancer samples and cell lines by polymerase chain reaction (PCR). Approximately 26% of patients showed microsatellite instability in two or more loci. BAT-26 locus showed no alteration in primary tumors. We detected a BAX mutation in one tumor sample and a TGFbetaRII mutation in one cell line. Our findings confirm the presence of the RER+ phenotype in sporadic ovarian cancer. The low rate of mutation in genes previously reported to be altered in colon and gastric cancer suggests that other not yet identified genes might be altered and could play a role in tumor progression and response to treatment in RER+ ovarian tumors.
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PMID:Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer. 1075 43

The tissue inhibitor of metalloproteinase-3 (TIMP-3), a recently cloned member of TIMP gene family, has been implicated in the negative regulation of tumor cell invasion and tumor growth. Down-regulation of this gene has been shown to occur in a mouse carcinogenesis model, suggesting that it might play a role in the tumor progression of some cancers. In this study, we used human gastric cancer cell lines to investigate whether TIMP-3 gene expression is suppressed in human gastric cancer. We examined whether aberrant DNA methylation of the 5'-CpG island of the TIMP-3 gene is involved in this cancer. Nine of 10 human gastric cancer cell lines completely lost TIMP-3 gene expression compared with normal samples. Southern blot analysis and bisulfite genomic sequencing revealed aberrant hypermethylation near the transcription-start site of the TIMP-3 gene in all cell lines lacking TIMP-3 expression. Treatment of these cell lines with the demethylating agent 5-aza-2'-deoxycytidine restored TIMP-3 gene expression. Our results suggest that the TIMP-3 gene is another early target of tumor-associated aberrant DNA methylation in human gastric carcinogenesis. Consequently, genetic silencing of TIMP-3 may lead to a more malignant and invasive phenotype in these cancer cells.
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PMID:Transcriptional inactivation of the tissue inhibitor of metalloproteinase-3 gene by dna hypermethylation of the 5'-CpG island in human gastric cancer cell lines. 1079 83

Alterations of protein tyrosine kinase are often associated with uncontrolled cell growth and tumor progression. Knowledge of the overall expression pattern of tyrosine kinases should prove beneficial in understanding the signaling pathways involved in gastric cancer oncogenesis and in providing possible biomarkers for gastric cancer progression. To establish a general tyrosine-kinase expression profile, degenerated polymerase chain reaction primers designed from the consensus catalytic kinase motifs were used to amplify protein tyrosine kinase molecules from gastric cancer tissues. We observed more than 50 tyrosine and serine/threonine kinases from matching pairs of gastric cancer tissue and normal mucosa. Based on this new kinase profile information, we selected the MKK4 gene for further immunohistochemical studies. Statistical analysis of MKK4 protein expression and clinicopathological features indicated that MKK4 kinase expression could serve as a significant prognostic factor for relapse-free survival and for overall survival. We demonstrated a simple and sensitive method for establishing protein tyrosine-kinase expression profiles of human gastric cancer tissues as well as for discovering novel and useful clinical biomarkers from such kinase expression profiles.
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PMID:Human gastric cancer kinase profile and prognostic significance of MKK4 kinase. 1085 23

Either p53 gene mutation or immunohistochemical detection of p53 protein has not been consistently shown to have prognostic significance in human cancers, including gastric carcinomas. One hypothesis to explain this inconsistency is that some p53 mutations and p53 protein accumulation are not indicative of tumor progression. To test this hypothesis, we categorized p53 status in 105 gastric carcinomas according to types of mutations, numerical scores of immunohistochemical staining (IHC), or combinations thereof. The p53 status was then correlated with metastasis to liver or peritoneum. Gastric cancers with no p53 mutations were significantly less likely to metastasize than tumors with mutations. Intermediate IHC scores were inversely associated with metastasis. A substantial number of gastric cancers (31 of 105) showed positive p53 immunostaining without detectable mutations (p53-/IHC+), which suggested an accumulation of wild-type p53 protein, and also a significantly lower risk for metastasis. After adjusting for depth of invasion and lymph node involvement, the p53-/IHC+ combination predicted low metastatic risk better than either p53- or IHC+ with intermediate scores. These findings suggest that an accumulation of wild-type p53 protein occurs in gastric cancer cells and represents a stress-response mechanism that lowers metastatic potential.
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PMID:Genetic and immunohistochemical analyses of p53 independently predict regional metastasis of gastric cancers. 1086

We examined genomic DNA from each of three human-derived gastric cancer cell lines, using the technique of restriction landmark genomic scanning (RLGS) which allows monitoring of approximately 2, 000 NotI landmarks. The resulting DNA spots from cancer cell DNA were compared with those in normal mucosa or gastric primary tumor. In all, 9 intense spots were detected from two of the three cancer cell lines. Two highly intensified spots were common in the two cancer cell lines and proven to be originated from DNA region containing the human c-myc proto-oncogene on chromosome 8. The degree of amplification of c-myc DNA was similar to each other and was estimated to be 60-fold as compared to those from normal mucosa DNA. On the basis of chromosome-assigned RLGS (CA-RLGS), other spots were assigned to each chromosome, such as one on chromosome 8, two each from chromosome 20, and three on one of chromosome 9-12. The remaining spot seems to be due to demethylation of a repetitive element. Twenty-four spot that were lost due to either homozygous deletion or methylation on corresponding NotI cleavage sites were commonly observed in all cancer cells. These spots were also assigned to each chromosome: one each from chromosome 2, 6, 7, 13, 14, 16, and 20, two each from chromosome 3 and 5, and nine from chromosome 9-12 by CA-RLGS. Many of the multi-copy spots corresponding to ribosomal RNA genes were greatly decreased due mainly to methylation on CpG islands along with minor rDNA variants, indicating that only minor rRNA genes may be silenced in these cancer cells. These results show that the present alterations detected by RLGS might be useful for identification of candidate genes inactivated or expressed unexpectedly in tumor development and tumor progression in the stomach.
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PMID:Detection of genetic alterations in the human gastric cancer cell lines by two-dimensional analysis of genomic DNA. 1089 39


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