Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer and this effect is mediated in part through inhibition of type 2 prostaglandin endoperoxide synthase/ cyclo-oxygenase (COX-2). In the present study, we demonstrate that COX-2 expression and PGE2 synthesis are up-regulated by an IGF-II/IGF-I receptor autocrine pathway in Caco-2 colon carcinoma cells. COX-2 mRNA and PGE2 levels are higher in proliferating cells compared with post-confluent differentiated cells and in cells that constitutively overexpress IGF-II. Up-regulation of COX-2 expression by IGF-II is mediated through activation of IGF-I receptor because: (i) treatment of Caco-2 cells with a blocking antibody to the IGF-I receptor inhibits COX-2 mRNA expression; (ii) transfection of Caco-2 cells with a dominant negative IGF-I receptor reduces COX-2 expression and activity. Also, the blockade of the PI3-kinase, that mediates the proliferative effect of IGF-I receptor in Caco-2 cells, inhibits IGF-II-dependent COX-2 up-regulation and PGE2 synthesis. Moreover, COX-2 expression and activity inversely correlate with the increase of apoptosis in parental, IGF-II and dominant-negative IGF-I receptor transfected cells. This study suggests that induction of proliferation and tumor progression of colon cancer cells by the IGF-II/IGF-I receptor pathway may depend on the activation of COX-2-related events.
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PMID:IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PGE2 synthesis in Caco-2 human colon carcinoma cells. 1111 29

Prostaglandin E2 (PGE2) has served as a surrogate end point biomarker in colorectal tumor progression. Colonic mucosa PGE2 levels of patients with colorectal adenomas or carcinomas have been shown to be higher than in control subjects. Our dose-finding study on piroxicam, a nonsteroidal anti-inflammatory drug with chemopreventive effects in preclinical colon carcinoma models, suggested that 7.5 mg/day was well tolerated and associated with significant depression of rectal mucosa PGE2 concentrations in comparison with baseline values. We therefore conducted a randomized Phase IIb cancer prevention clinical trial to investigate the chemopreventive properties of piroxicam in patients with a history of resected colorectal adenomatous polyps. After a 2-month run-in period, 47 participants were randomized to piroxicam at a dose of 7.5 mg/day, and 49 were randomized to a placebo. Rectal biopsy specimens were taken at the initial visit, at 2 months later during the run-in period, and at 6, 12, and 24 months after the start of the interventions. Mean PGE2 concentrations in the rectal mucosa of the piroxicam-treated patients differed significantly between visits (P < 0.001), and the values at the 6-month visit (P < 0.001) and 12-month visit (P = 0.005) differed significantly from the average baseline value. Unfortunately, we observed an incidence of adverse gastrointestinal side effects in patients treated with 7.5 mg/day of piroxicam similar to that seen for arthritis patients treated with 20 mg/day. Consequently, the gastrointestinal toxicities appear to override the potential benefit that piroxicam may offer as a long-term colon cancer chemopreventive agent.
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PMID:Effects of piroxicam on prostaglandin E2 levels in rectal mucosa of adenomatous polyp patients: a randomized phase IIb trial. 1114 13

The expression of Fas ligand (FasL) by tumor cells has been reported to have multiple, conflicting effects on tumor growth. The majority of the data support the theory that FasL expressing tumor cells evade immune surveillance by killing T cells expressing Fas. However, the role of the humoral immune-blockade by FasL expressing tumor cells has not been assessed. Using immune-competent mice, we observed that FasL expressing tumor cells reduced the antitumor antibody production together with the T and B cell content of the spleen in these mice. Further, to determine if the expression of FasL in the environment of the tumor suppresses the humoral antitumor immune response and influences tumor growth, a mouse model lacking T cells was used. To assess whether a local reduction of FasL could reduce tumor progression, a plasmid encoding antisense FasL cDNA was delivered directly into a growing tumor (SW620 colon carcinoma). Intratumoral delivery of the plasmid was able to transfect tumor cells, stromal cells, and peritumoral muscle cells. This antisense FasL tumor tissue transfection persisted for at least 25 days, produced a systemic decrease in soluble FasL, and resulted in a 50% reduction in the rate of tumor growth when compared with tumor tissue of the control groups. These results suggest that direct transfection of antisense FasL cDNA impairs FasL translation in tumor and stromal cells, and can inhibit tumor progression by impairing the FasL-mediated, stromal cell-assisted, tumor counter-attack.
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PMID:Direct in vivo transfection of antisense Fas-ligand reduces tumor growth and invasion. 1131 92

Quantitative analysis of the process of tumor angiogenesis was performed in a new animal model of tumor microcirculation, in which colon carcinoma cells were inoculated into the peritoneal cavity of rats. Time-dependent changes in the microvascular architecture of mesenteric microvessels of tumor-bearing rats were visualized using an intravital microscope. Simultaneously, the expression of vascular endothelial growth factor (VEGF) by the tumor cells and VEGF secretion into ascites were analyzed. The results showed that VEGF increases microvascular permeability and stimulates the growth of microvessels into the tumor and that the spatial and temporal concentration of VEGF is strongly correlated. Such a correlation was stronger in the early angiogenic stages of tumor growth than in the subsequently occurring multiple metastatic stage, when VEGF was still observed at a high level in tumor surroundings. Thus, VEGF is suggested to be primarily involved in the pathophysiological control of angiogenesis accompanying tumor progression.
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PMID:Vascular endothelial growth factor (VEGF) expression regulates angiogenesis accompanying tumor growth in a peritoneal disseminated tumor model. 1149 Oct 18

Loss of DNA mismatch repair (MMR) increases the risk of spontaneous mutations. We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR-proficient) sublines were exposed for varying periods of time to an environment of <0.1% O2 and pH as low as 6.1. When a population containing 5% MMR-deficient cells and 95% MMR-proficient cells was subjected to hypoxia for 72 h, the MMR-deficient cells were enriched by a factor of 2-fold in the surviving population, whereas no enrichment was detected in cells maintained under aerobic conditions. The potential of hypoxia to destabilize the genome was determined by measuring the frequency of clones in the surviving population resistant to very high concentrations of 6-thioguanine or cisplatin. A 72-h exposure to hypoxia did not increase the frequency of resistant clones in the MMR-proficient cells but produced a 7.8-fold increase in 6-thioguanine-resistant clones and a 2.5-fold increase in cisplatin-resistant clones in the MMR-deficient cells. Loss of MMR increased the frequency of mutations in a reporter vector sensitive to frameshift mutations in a microsatellite sequence. Exposure to hypoxia for a time period as short as 48 h further increased the number of mutations in both cell types, but the absolute number of mutants was higher in the MMR-deficient cells. These results indicate that hypoxia and its accompanying low pH enrich for MMR-deficient cells and that loss of MMR renders human colon carcinoma cells hypersensitive to the ability of hypoxia to induce microsatellite instability and generate highly drug-resistant clones in the surviving population.
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PMID:Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair. 1160

Selective COX-2 inhibitors reduce adenoma formation and cancer progression in rodent models of colorectal cancer. To assess the therapeutic activity of selective COX-2 inhibitors, we tested the effect of SC-58125 treatment on the growth of human colon carcinoma cells in nude mice. Delaying treatment by 2, 4, or 7 weeks following implantation of the carcinoma cells resulted in a significant inhibition of tumor growth. Furthermore, short-term (48 hours) treatment with SC-58125 was sufficient to attenuate tumor growth for up to 15 days. SC-58125 treatment did not alter the rate at which cells underwent apoptosis, but did result in a delayed progression through the cell cycle at the G(2)/M transition. Accordingly, p34(cdc2) protein levels and activity were decreased following SC-58125 treatment. We conclude that SC-58125 primarily exerts a cytostatic effect in vivo, which is likely to be mediated through inhibition of progression through the G(2)/M phase of the cell cycle.
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PMID:A cyclooxygenase-2 inhibitor (SC-58125) blocks growth of established human colon cancer xenografts. 1168 54

Activated Ras but not Raf can transform RIE-1 and other epithelial cells, indicating the critical importance of Raf-independent effector function in Ras transformation of epithelial cells. To elucidate the nature of these Raf-independent activities, we utilized representational difference analysis to identify genes aberrantly expressed by Ras through Raf-independent mechanisms in RIE-1 cells. We identified a total of 22 genes, both known and novel, whose expression was either activated or abolished by Ras but not Raf. The genes up-regulated encode proteins involved in protein or DNA synthesis, regulation of protease activity, or ligand binding, whereas those genes down-regulated encode actin cytoskeletal-, extracellular matrix-, and gap junction-associated proteins, and transmembrane receptor- or cytokine-like proteins. These results suggest that a key function of Raf-independent signaling involves deregulation of gene expression. We further characterized transgelin as a gene whose expression was abolished by Ras. Transgelin was identified previously as a protein whose expression was lost in virally transformed cell lines. We show that this loss is regulated at the level of gene expression and that both Raf-dependent and Raf-independent pathways are required to cause Ras down-regulation of transgelin in RIE-1 cells, whereas Raf alone is sufficient to cause its loss in NIH 3T3 fibroblasts. We also found that Ras-dependent and Ras-independent mechanisms can cause the down-regulation of transgelin in human breast and colon carcinoma cells lines and patient-derived tumor samples. We conclude that loss of transgelin gene expression may be an important early event in tumor progression and a diagnostic marker for breast and colon cancer development.
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PMID:Loss of transgelin in breast and colon tumors and in RIE-1 cells by Ras deregulation of gene expression through Raf-independent pathways. 1177 51

The Wnt signaling pathway modulates the transcription of genes linked to proliferation, differentiation and tumor progression. beta-Catenin-Tcf (BCT)-dependent Wnt signaling is influenced by the short-chain fatty acid sodium butyrate, which induces growth arrest and/or maturation of colonic carcinoma cells. We have compared the effects of sodium butyrate on BCT-dependent signaling in 2 colon carcinoma cell lines that differ in their physiologic response to butyrate, with SW620 cells responding to butyrate by undergoing terminal differentiation and apoptosis, and HCT-116 cells undergoing reversible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway activation, with adenomatous polyposis coli (APC) mutant SW620 cells having high levels of BCT complexes and APC wild-type HCT-116 cells having mutant beta-catenin, low levels of BCT complexes and correspondingly higher levels of free Tcf. We have demonstrated that in SW620 cells, butyrate downregulates BCT-dependent expression of the Tcf-TK, matrilysin and cyclin D1 promoters, whereas in HCT-116 cells, butyrate upregulates expression of these promoters. Cotransfection with expression vectors that interfere with the Wnt pathway suggests that butyrate enhances BCT complex-DNA binding. Butyrate reduces the expression of Tcf4 in HCT-116 cells, consistent with the induction by butyrate of Tcf-repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT-116 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyrate.
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PMID:Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate. 1177 42

Vascular endothelial growth factor (VEGF), an important angiogenic factor, regulates cell proliferation, differentiation, and apoptosis through activation of its tyrosine-kinase receptors, such as Flt-1 and Flk-1/Kdr. Human malignant mesothelioma cells (HMC), which have wild-type p53, express VEGF and exhibit cell growth increased by VEGF. Here, we demonstrate that early transforming proteins of simian virus (SV) 40, large tumor antigen (Tag) and small tumor antigen (tag), which have been associated with mesotheliomas, enhanced HMC proliferation by inducing VEGF expression. SV40-Tag expression potently increased VEGF protein and mRNA levels in several HMC lines. This effect was suppressed by the protein synthesis inhibitor, cycloheximide. Inactivation of the VEGF signal transduction pathway by expression of soluble form of Flt-1 inhibited Flk-1/Kdr activation and HMC proliferation induced by SV40 early genes. Experiments with SV40 mutants revealed that SV40-Tag, but not -tag, is involved in the VEGF promoter activation. However, concomitant expression of SV40-tag enhanced Tag function. In addition, SV40-Tag expression sustained VEGF induction in colon carcinoma cell line (CCL)-233, which have wild-type p53, but not in CCL-238, which lack functional p53. These data indicate that VEGF regulation by SV40 transforming proteins can represent a key event in SV40 signaling relevant for tumor progression.
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PMID:Enhanced expression of vascular endothelial growth factor (VEGF) plays a critical role in the tumor progression potential induced by simian virus 40 large T antigen. 1197 50

The majority of tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) exhibit a mutator phenotype characterized by widespread microsatellite instability (MSI) and somatic mutations in repeated sequences in several cancer-associated genes. An inverse relationship between MSI and chromosomal instability (CIN) has been demonstrated and HNPCC-associated tumors are generally characterized by diploid or near-diploid cells with few or no chromosomal rearrangements. We have studied MSI, somatic mutations in repeat-containing genes, DNA-ploidy, and cytogenetic aberrations in a colon carcinoma from a patient with a germline MLH1 mutation. Mutations in coding repeats were assessed in 10 macroscopically separate areas of the primary tumor and in two lymph nodes. Some of the genes studied (E2F4, MSH3, MSH6, TCF4, and TGFBRII) showed a consistent lack of mutations, whereas others (BAX, Caspase-5 and IGFIIR) displayed alterations in some tumor regions but not in others. The tumor had DNA-index 1.1-1.2 and a stable, aberrant karyotype with extra copies of chromosomes 7 and 12 and the structural aberrations i(1q), der(20)t(8;20), and der(22)t(1;22). The finding of CIN, MSI, and somatic mutations in coding repeats in this tumor suggests that these phenomena may act together in HNPCC tumorigenesis. Furthermore, the observed intratumoral heterogeneity of mutations in coding repeats implies these changes occur late in tumorigenesis and, thus, probably play a role in tumor progression rather than initiation.
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PMID:Cytogenetic aberrations and heterogeneity of mutations in repeat-containing genes in a colon carcinoma from a patient with hereditary nonpolyposis colorectal cancer. 1199 96


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