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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For tumor progression, a cascade of linked sequential biological events is essential. We tried to test whether biological therapy can modulate specific biological phenotypes and increase the anti-tumor effect when combined with chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7, AGS) were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding growth factor inhibitor, Tranexamic acid as a plasmin inhibitor, Lovastatin as an adhesion inhibitor and Adriamycin as a chemotherapeutic agent were selected. The effects of each drug on colony formation and tumor cell proliferation were evaluated by soft agar assay and cell proliferation assay, respectively to test direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA, while MMPs activity was evaluated by zymography. PPS suppressed the colony-forming activity as much as Adriamycin did, but it showed only cytostatic effects in cell proliferation assay. Migration capacity using Boyden chamber assay was more closely correlated with adhesive capacity than uPA or MMP-2 expression. The motility inhibitory effect of Tranexamic acid was observed in the YCC-7 cell line, which expressed all the required biological phenotypes for migration. In AGS, with high cell motility and adhesiveness, the adhesion was inhibited by Lovastatin and most of the inhibitory effect was recovered by Mevalonate. When PPS was combined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while that for a single treatment of PPS or Adriamycin was 40% and 22%, respectively (p=0.001). When we combined Tranexamic acid and Adriamycin, we observed the synergistic effect in YCC-3 and YCC-7, while no combined effect was found in YCC-1. The combination of Lovastatin and Adriamycin did not show any combined effects in any of the cell lines. In conclusion, a synergistic anti-proliferative effect (chemo-sensitization) with combined chemo-biotherapy was found in cancer cells with specific biological target, MK. The anti-motility effect was the greatest when the gastric cancer cells expressed all the specific biological phenotypes.
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PMID:Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer. 1040 90

Tumor invasion marks a critical point in cancer progression; it is a harbinger of morbidity and mortality. Thus, the cellular events that enable the invasive phenotype are under intense investigation. Epstein-Barr virus (EBV) is associated with a number of cancers, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC) and is suspected to contribute to their tumorigenesis. On average, 8% of gastric carcinomas have been shown to carry this virus. To explore whether the presence of EBV in gastric carcinoma contributes to tumor progression in this predominantly invasive carcinoma, we examined a panel of 2 in vitro EBV-infected human gastric cancer cell line sublines and their mock-infected AGS parental control line. We found EBV infection caused a marked increase in transmigration of a Matrigel barrier (415% and 303%, p < 0.05, for the 2 infected lines). This correlated with increased motility of these sublines (233% and 140%, p < 0.05). As this pattern of increased motility leading to a more pronounced enhancement of invasion has been noted in other tumor cells, we explored the roles of autocrine signaling pathways previously implicated in carcinoma motility and invasion. Inhibitors to the epidermal growth factor receptor (EGFR) (PD153035), phospholipase C (PLC) (U73122), extracellular-signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) (PD089035) and PI-3 kinase (Wortmannin) were not informative. These data suggest that EBV increases migration of AGS cells by a mechanism independent of these autocrine growth factor-induced pathways. Instead, we found that the EBV-infected cells presented increased focal adhesion kinase (FAK) phosphorylation. These findings suggest a role for integrin-mediated signaling in promoting EBV-associated invasiveness.
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PMID:EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness. 1211 96

Rebamipide accelerates healing of gastric ulcers and gastritis but its actions on gastric cancer are not known. Survivin, an anti-apoptosis protein, is overexpressed in stem, progenitor, and cancer cells. In gastric cancer, increased and sustained survivin expression provides survival advantage and facilitates tumor progression and resistance to anti-cancer drugs. Aurora-B kinase is essential for chromosome alignment and mitosis progression but surprisingly its role in gastric cancer has not been explored. We examined in human gastric cancer AGS cells: (1) survivin expression, (2) localization of survivin and Aurora-B, (3) cell proliferation, and (4) effects of specific survivin siRNA and/or rebamipide (free radical scavenging drug) on survivin and Aurora-B expression and cell proliferation. Survivin and Aurora-B are strongly expressed in human AGS gastric cancer cells and co-localize during mitosis. Survivin siRNA significantly reduces AGS cell viability. Rebamipide significantly downregulates in AGS cell survivin expression, its association with Aurora-B and cell proliferation. Rebamipide-induced downregulation of survivin is at the transcription level and does not involve ubiquitin-proteasome pathway.
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PMID:Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B. 1599 41

Cellular prion protein (PrP(C)), a glycosylphosphatidylinositol-anchored membrane protein, was found in our lab to be widely expressed in gastric cancer cell lines. In order to evaluate its biological significance in human gastric cancer, we investigated its expression in a large series of gastric tissue samples (n = 124) by immuno histochemical staining with the monoclonal antibody 3F4. Compared with normal tissues, gastric adenocarcinoma showed increased PrP(C) expression, correlated with the histopathological differentiation (according to the WHO and Lauren classifications) and tumor progression (as documented by pTNM staging). To better understand the underlying mechanism, we introduced the PrP(C) and two pairs of RNAi into the poorly differentiated gastric cancer cell line AGS and found that PrP(C) suppressed ROS and slowed down apoptosis in transfected cells. Further study proved that the apoptosis-related protein Bcl-2 was upregulated whereas p53 and Bax were downregulated in the PrP(C)-transfected cells. A reverse effect was observed in PrP(C) siRNA-transfected cells. These results strongly suggested that PrP(C) might play a role as an effective antiapoptotic protein through Bcl-2-dependent apoptotic pathways in gastric cancer cells. Further study into the mechanism of these relationships might enrich the knowledge of PrP, better our understanding of the nature of gastric carcinoma, and further develop possible strategies to block or reverse the development of gastric carcinoma.
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PMID:Overexpression of PrPC and its antiapoptosis function in gastric cancer. 1658 85

Abelson interactor protein-1 (ABI1) is a promising candidate tumor suppressor, and plays critical roles both in the pathogenesis of BCR-Abl-induced leukemia and in the spread of several solid tumors. The expression of ABI1 and its role in cancer progression and prognosis are largely unknown in the majority of solid tumors, including gastric cancer. In this study, we analyzed the correlation between ABI1 expression and the clinicopathological characteristics, tumor progression, and prognosis of patients with gastric carcinoma. Tissue specimens were from 103 gastric cancer patients who underwent gastrectomy in our hospital between January 2000 and December 2007. Among them 59 tumor tissue samples were matched with normal tissue samples. The expression of ABI1 protein was measured using immunohistochemical staining of paraffin-embedded tissue specimens. Meanwhile, quantitative real-time RT-PCR and Western blotting were used to identify the expression of ABI1 in human gastric normal mucosal cell line (GES-1) and gastric cancer cell lines (N87, AGS). We performed a statistical analysis of the potential correlation between ABI1 expression and the patients' clinicopathological characteristics, 5-year survival, and median survival time. The immunohistochemical staining results of 59 patients showed that ABI1 was expressed in 28.8% (17/59) of gastric cancer tissues, compared to 91.5% (54/59) of normal samples. ABI1 expression in 103 patients was strongly correlated with tumor differentiation, clinical stage, and lymph node status (P < 0.01). The 5-year survival rate was 15.3% in the ABI1-negative group and 63.7% in the ABI1-positive group. Median survival time in the ABI1-negative and ABI1-positive groups was 25.0 months (95% CI: 19.7-30.3) and 74.0 months (95% CI: 54.6-93.3), respectively. There was a significant difference between the two groups (chi(2) = 10.888, P = 0.001). Furthermore, we found that ABI1 expressed lowly in poor differentiated AGS, whereas highly in GES-1 and well-differentiated N87. Downregulation of ABI1 expression in human gastric carcinoma may play a critical role in tumor progression and in determining patient prognosis. ABI1 may be a useful diagnostic or prognostic molecular biomarker, and might be a potential target for therapeutic intervention.
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PMID:Downregulation of ABI1 expression affects the progression and prognosis of human gastric carcinoma. 1955 84

The c-Myc promoter binding protein 1 (MBP-1) is a transcriptional suppressor of c-myc expression and involved in control of tumorigenesis. Gastric cancer is one of the most frequent neoplasms and lethal malignancies worldwide. So far, the regulatory mechanism of its aggressiveness has not been clearly characterized. Here we studied roles of MBP-1 in gastric cancer progression. We found that cell proliferation was inhibited by MBP-1 overexpression in human stomach adenocarcinoma SC-M1 cells. Colony formation, migration, and invasion abilities of SC-M1 cells were suppressed by MBP-1 overexpression but promoted by MBP-1 knockdown. Furthermore, the xenografted tumor growth of SC-M1 cells was suppressed by MBP-1 overexpression. Metastasis in lungs of mice was inhibited by MBP-1 after tail vein injection with SC-M1 cells. MBP-1 also suppressed epithelial-mesenchymal transition in SC-M1 cells. Additionally, MBP-1 bound on cyclooxygenase 2 (COX-2) promoter and downregulated COX-2 expression. The MBP-1-suppressed tumor progression in SC-M1 cells were through inhibition of COX-2 expression. MBP-1 also exerted a suppressive effect on tumor progression of other gastric cancer cells such as AGS and NUGC-3 cells. Taken together, these results suggest that MBP-1-suppressed COX-2 expression plays an important role in the inhibition of growth and progression of gastric cancer.
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PMID:MBP-1 suppresses growth and metastasis of gastric cancer cells through COX-2. 1984 62

Prostaglandin (PG) E(2) promotes gastrointestinal carcinogenesis and tumor progression. We determined the correlations between pattern of expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a catabolic enzyme for biological inactivation of PGE(2), in gastric adenocarcinoma and various clinicopathological factors and patient outcome in an attempt to elucidate its biological significance. In 35 of 71 cases of gastric adenocarcinoma, expression of 15-PGDH protein was reduced in tumor tissues. Multivariate analysis revealed reduction of 15-PGDH expression to be an independent predictor of poor survival. The proportion of Ki67-positive cells in 15-PGDH-negative adenocarcinoma was higher than that in 15-PGDH-positive adenocarcinoma. No differences were found in clinicopathological parameters between patients with cyclooxygenase-2 (COX-2)-positive tumors and those with COX-2 negative tumors. In an in vitro study, use of specific siRNA to silence 15-PGDH or a specific inhibitor of 15-PGDH enhanced cell proliferation in the gastric cancer cell line AGS, which expresses 15-PGDH. These findings suggest that reduction of 15-PGDH is an independent predictor of poor survival associated with enhancement of cell proliferation in gastric adenocarcinoma.
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PMID:Reduction of 15-hydroxyprostaglandin dehydrogenase expression is an independent predictor of poor survival associated with enhanced cell proliferation in gastric adenocarcinoma. 1991 58

Nicotine is shown to be one of the carcinogenic agents for gastric cancer. Perturbation of epithelial-mesenchymal transition (EMT) results in loss of intracellular adhesions leading to tumor progression. In this study, we examined the underlying mechanism of the long-term effects of nicotine on tumor progression in human gastric cancer cells. Nicotine activated 5-lipoxygenase (5-LOX) in three gastric cancer cell lines (MKN-45, MKN-28 and AGS). Cells treated with nicotine dose- and time-dependently induced cell proliferation, invasion and suppressed apoptosis. In addition, cell cycle progression analysis revealed that activation of 5-LOX modulated the G1/S phase transition regulatory proteins and caused cell proliferation. MK886 (5-LOX activating protein inhibitor) mediated the induction of apoptosis by elevation of caspase-3 and Bax/Bcl2 ratio. Abrogation of 5-LOX repressed featured molecular markers of EMT (inactivation of E-cadherin and activation of transcriptional repressor Snail). Blockade of 5-LOX signaling resulted in downregulation of cyclin D1, matrix metalloproteinase (MMP-7, -9), urokinase plasminogen activator (uPA) and its receptor (uPAR), and pro-apoptotic proteins. Furthermore, suppression of Snail and induction of E-cadherin is extracellular signal-regulated kinase (Erk)-dependent. Thus, we conclude that the promotion effect of nicotine on cancer cell progression and EMT is mediated by Erk/5-LOX signaling pathway.
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PMID:Activation of 5-lipoxygenase is required for nicotine mediated epithelial-mesenchymal transition and tumor cell growth. 2006 Oct 81

Although Rho family GTPases RhoA, RhoB and RhoC share more than 85% amino acid sequence identity, they may play distinct roles in tumor progression. RhoA and RhoC have been suggested to have positive effects on tumor progression, but the role of RhoB in cancer, particularly in gastric cancer, remains unclear. In our study, we have examined the expression levels of these three Rho GTPases in a large panel of specimens from gastric cancer patients by immunohistochemistry. We found that RhoA and RhoC expression were significantly elevated, while RhoB was reduced or absent, in surgically removed gastric cancer tissues when compared to normal gastric tissues. The significant reduction of RhoB expression was confirmed in another group of gastric cancer samples in comparison to the adjacent non-neoplastic tissues. Then we transfected the plasmids containing RhoA, RhoB or RhoC cDNA into two gastric cancer cell lines, SGC7901 and AGS cells, respectively. By overexpression experiments, we found that RhoA promoted the gastric cancer cell proliferation and RhoC stimulated migration and invasion of the cancer cell. RhoB expression, however, significantly inhibited the proliferation, migration and invasion of the gastric cancer cells and also enhanced the chemosensitivity of these cells to anticancer drugs. It appears that RhoB plays an opposing role from that of RhoA and/or RhoC in gastric cancer cells. Our work suggests that RhoB may play a tumor suppressor role and subsequently may have potential implications in future targeted therapy.
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PMID:A distinct role of RhoB in gastric cancer suppression. 2047 33

RAB25 plays an important role in tumor progression and aggressiveness; altered RAB25 expression may cause human cancer. As the underlying mechanism of RAB25-mediated carcinogenesis in various tumor types progressively comes to light, RAB25 is expected to represent a novel therapeutic target. However, the regulation of RAB25 expression per se has not yet been described. Here we have firstly identified and characterized the human RAB25 promoter. Using PCR-based chromatin accessibility and chromatin immunoprecipitation (ChIP) assays, an open chromatin conformation (-173/+17) was detected around the transcription start site of the RAB25 gene. Deletion constructs of the 5' flanking region were fused to a luciferase reporter gene. After transient transfection in gastric cancer cell line AGS, a CRE (-67/-58) binding CREB was identified in the core promoter region. Electrophoretic mobility shift (EMSA) and ChIP assays demonstrated that CREB binds to the core promoter. Deletion of CREB consensus sequence resulted in the total loss of the promoter activity. Moreover, we have also found forskolin, PKA activator, could enhance open chromatin accessibility, by which to expose the CRE and facilitate phosphorylation of CREB, which in turn recruits co-factor CBP and Brg I and then results in a more open chromatin configuration associated with local histone modification, finally heightening RAB25 expression and strengthening its promoter activity. Therefore, the present study delineates the fundamental elements of a core promoter structure that will be helpful for future studies regarding the regulation of RAB25 gene.
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PMID:A CRE that binds CREB and contributes to PKA-dependent regulation of the proximal promoter of human RAB25 gene. 2107 12


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