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

Immunoprevention is a fresh approach to cancer prevention based on the stimulation of the immune system before tumor onset. Immunoprevention was effective in various models of carcinogen-induced or autochthonous tumor progression. Vaccines made of cells or DNA plasmids combined with appropriate adjuvants completely blocked mammary carcinogenesis in HER-2/neu transgenic mice. At variance with cancer immunotherapy, the mediators of immunoprevention are antibodies and T-cell-derived cytokines, rather than cytotoxic T-cells. Immunopreventive approaches and chemoprevention with tamoxifen or cyclooxygenase-2 inhibitors can be combined advantageously. The success obtained in preclinical studies suggests that cancer immunoprevention should progress to clinical testing.
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PMID:Cancer immunoprevention. 1655 76

Lack of reliable prognostic markers hinders accurate prediction of disease progression in prostate cancer. The inducible proinflammatory enzyme cyclooxygenase-2 (COX-2) is implicated in prostate carcinogenesis, but its role in cancer progression is less clear. We examined whether COX-2 expression evaluated by immunohistochemistry (IHC) in radical prostatectomy (RP) specimens can predict biochemical recurrence. Archival prostate cancer specimens (n = 60) were obtained from patients who underwent RP, but had not received neoadjuvant hormonal therapy. Twenty-three patients had biochemical or clinical recurrence (mean time of recurrence: 38.2 months), and 37 patients were recurrence free (mean follow-up: 95 months). COX-2 expression was determined by IHC, using an anti-COX-2 antibody. Three individuals scored the staining independently, as high- or low-expression. COX-2 was expressed in prostate cancer cells, in adjacent normal glands and in specimens from patients who later progressed. At 62-months follow-up, COX-2 staining predicted progression with 82.4% sensitivity and 81.3% specificity. Sensitivity (86.4%) and specificity (86.7%) improved at > or = 100-months follow-up. In univariate analysis, Gleason score, preoperative PSA, extraprostatic extension, margin, seminal vesicle invasion, and high COX-2 expression were significant predictors of biochemical recurrence (p < 0.05). In multivariate analysis, preoperative PSA (hazard ratio/unit PSA change 1.080; p = 0.0036) and COX-2 expression (hazard ratio 16.442; p < 0.0001) were independent prognostic indicators. Patients with PSA > 7 ng/ml and high COX-2 expression had the highest probability of recurrence (Kaplan-Meier analysis). COX-2 expression is an independent predictor of prostate cancer progression following RP and underscores the significance of inflammatory factors in this process.
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PMID:Cyclooxygenase-2 (COX-2) expression is an independent predictor of prostate cancer recurrence. 1655 96

Cyclooxygenase-2 (COX-2) inhibitors are being tried in clinics for cancer treatment. One of the mechanism by which COX-2 inhibitors suppress cancer progression is suggested to be inhibition of angiogenesis. To investigate how COX-2 inhibitors affect regulation of angiogenic factors, we studied alterations in VEGF levels in sera and plasma during COX-2 inhibitor treatment in breast cancer patients. Serum and plasma VEGF levels were monitored in 48 patients treated with the COX-2 inhibitor celecoxib together with 5-FU, epirubicine, cyclophosphamide (FEC). Serum VEGF levels showed decreases on day 3 of the first cycle (P<0.0001), followed by increases after 3 weeks (P<0.0001). Plasma VEGF levels did not show decreases on day 3 but showed increases after 3 weeks (P<0.05). The increases of VEGF levels in sera and plasma continued until the next cycle of the treatment. In patients treated with FEC alone (without celecoxib) did not show increases in serum VEGF levels during the treatment. Our data showed that treatment with COX-2 inhibitors decreased serum VEGF levels at an early time and increased VEGF levels in serum and plasma at a late time in breast cancer patients. Further studies are necessary to elucidate how COX-2 inhibitors regulate production of VEGF in different cells and different tissues in cancer patients.
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PMID:Increases in circulating VEGF levels during COX-2 inhibitor treatment in breast cancer patients. 1680 97

The regulation of tumor progression towards its malignancy needs the interplay among several cytokines, growth factors, and enzymes, which are controlled in the tumor microenvironment. Here, we report that osteopontin, a small integrin-binding ligand N-linked glycoprotein family of calcified extracellular matrix-associated protein, regulates prostate tumor growth by regulating the expression of cyclooxygenase-2 (COX-2). We have shown that osteopontin stimulates the activation of protein kinase C alpha/nuclear factor-inducing kinase/nuclear factor-kappaB-dependent signaling cascades that induces COX-2 expression, which in turn regulates the prostaglandin E(2) production, matrix metalloproteinase-2 activation, and tumor progression and angiogenesis. We have revealed that suppression of osteopontin-induced COX-2 expression by the nonsteroidal anti-inflammatory drug celecoxib or blocking the EP2 receptor by its blocking antibody resulted in significant inhibition of cell motility and tumor growth and angiogenesis. The data also showed that osteopontin-induced mice PC-3 xenograft exhibits higher tumor load, increased tumor cell infiltration, nuclear polymorphism, and neovascularization. Interestingly, use of celecoxib or anti-EP2 blocking antibody drastically suppressed osteopontin-induced tumor growth that further indicated that suppression of COX-2 or its metabolites could significantly inhibit osteopontin-induced tumor growth. Human clinical prostate cancer specimen analysis also supports our in vitro and animal model studies. Our findings suggest that blockage of osteopontin and/or COX-2 is a promising therapeutic approach for the inhibition of prostate tumor progression and angiogenesis.
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PMID:The crucial role of cyclooxygenase-2 in osteopontin-induced protein kinase C alpha/c-Src/IkappaB kinase alpha/beta-dependent prostate tumor progression and angiogenesis. 1681 37

S100A2 is considered a putative tumor suppressor due to its loss or down-regulation in several cancer types. However, no mechanism has been described for the tumor suppressor role of S100A2. In this study, ectopic expression of S100A2 in the human malignant squamous cell carcinoma cell line KB resulted in a significant inhibition of proliferation, migration, and invasion. Moreover, S100A2 significantly reduced the number of colonies (>or=0.5 mm) formed in semisolid agar and decreased tumor growth and burden in nude mice. cDNA microarray analysis was used to compare mRNA expression profiles of vector- and S100A2-expressing isogenic cells. Among the genes deregulated by S100A2, the expression of cyclooxygenase-2 (COX-2) mRNA was significantly suppressed by S100A2 (2.4-fold). Western blot analysis confirmed that S100A2 reduced the expression of COX-2 protein in stably and transiently transfected KB and RPMI-2650 cells. COX-2 is frequently overexpressed in various types of cancer and plays an important role in tumor progression. Partial restoration of COX-2 expression attenuated the antitumor effect of S100A2 both in vitro and in vivo. Although the interplay between S100A2 and COX-2 remains to be clarified, these findings first showed a potent antitumor role of S100A2 in squamous cell carcinoma partly via reduced expression of COX-2.
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PMID:Cyclooxygenase-2 is involved in S100A2-mediated tumor suppression in squamous cell carcinoma. 1690 93

Cyclooxygenase-2 (Cox-2), the gastrin-release peptide (GRP) and its cognate receptor (GRP-R) are overexpressed in a significant percentage of colorectal carcinomas and are associated with cell growth, invasiveness and tumor progression. However, a molecular link between all of them in adenocarcinomas has not been established. Here, we show that bombesin (BBS), a GRP homolog, stimulates the expression of Cox-2 mRNA and protein in human colon adenocarcinoma Caco-2 cells, resulting in enhanced release of prostaglandin E(2). These effects were markedly inhibited by the specific BBS antagonist RC-3940-II. BBS promotes the activation of the nuclear factor of activated T cells (NFAT) through a Ca(2+)/calcineurin (Cn)-linked pathway. Upon BBS stimulation, the NFATc1 isoform translocates into the nucleus with a concomitant increase in NFATc1 binding to two specific recognition sites in the promoter region of the Cox-2 gene. Furthermore, inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBS-stimulated cells. Interestingly, BBS pretreatment strongly enhances the invasive capacity of carcinoma cells, effect which was inhibited by a Cox-2-specific inhibitor. These findings provide the first evidence for the involvement of the Ca(2+)/Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2.
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PMID:Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells. 1690 8

Prostaglandin E(2) (PGE(2)), one of the major metabolites of cyclooxygenase-2, has been implicated in tumorigenesis and tumor progression in several human cancers, including colorectal and lung. Here, we show that one of the PGE(2) receptors, the EP4 receptor, plays an important role in metastasis in both of these tumor types. Using i.v. injected Lewis lung carcinoma (3LL), we found that tumor metastasis to lung was significantly reduced when mice were treated with a specific EP4 antagonist ONO-AE3-208 or when EP4 receptor expression was knocked down in the tumor cells using RNA interference technology. Host EP4 receptors also contributed to tumor metastasis and tumor growth with decreased metastasis and tumor growth observed in EP4 receptor knockout animals. In vitro tumor cell adhesion, motility, invasion, colony formation, and Akt phosphorylation were all significantly inhibited when 3LL cells were treated with the EP4 receptor-specific antagonist. When the cells were treated with an EP4-specific agonist (AE1-734), we observed a worsening of these same features in vitro. Treatment with ONO-AE3-208 also profoundly decreased liver metastases after intrasplenic injection of MC26 colon cancer cells. Our data show that selective antagonism of EP4 receptor signaling results in a profound reduction in lung and colon cancer metastasis. Selective antagonism of the EP4 receptor may thus represent a novel therapeutic approach for the treatment of cancer and especially its propensity to metastasize.
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PMID:Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. 1701 24

Cyclooxygenase-2 (COX-2) represents an important target for treatment and prevention of colorectal cancer. Although COX-2 signaling is implicated in promoting tumor cell growth and invasion, the molecular mechanisms that mediate these processes are largely unknown. In this study, we show that the RhoA pathway mediates COX-2 signaling to disrupt the formation of adherens junctions and increase cell motility. Disruption of adherens junctions promotes tumor cell invasion and metastasis and is often associated with tumor progression. We detected high levels of RhoA activity in HCA-7 colon carcinoma cells that constitutively express COX-2. Inhibition of COX-2 significantly reduced the levels of RhoA activity in HCA-7 cells, suggesting that constitutive expression of COX-2 stimulates RhoA activity. Interestingly, inhibition of COX-2 or silencing of COX-2 expression with small interfering RNA (siRNA) stimulated the formation of adherens junctions, concomitant with increased protein levels of E-cadherin and alpha-catenin. Furthermore, inhibition of RhoA or silencing of RhoA expression with siRNA increased the levels of E-cadherin and alpha-catenin. Inhibition of Rho kinases (ROCK), the RhoA effector proteins, also increased levels of E-cadherin and alpha-catenin and stimulated formation of adherens junctions. The motility of HCA-7 cells was significantly decreased when COX-2 or RhoA was inhibited. Therefore, our data reveal a novel molecular mechanism that links COX-2 signaling to disrupt the formation of adherens junctions; COX-2 stimulates the RhoA/ROCK pathway, which reduces levels of E-cadherin and alpha-catenin leading to disruption of adherens junction formation and increased motility. Understanding of COX-2 downstream signaling pathways that promote tumor progression is crucial for the development of novel therapeutic strategies.
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PMID:RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility. 1717 65

To evaluate the expressions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in thyroid neoplasms in a Korean population, we studied a total of 154 cases: papillary carcinoma of classical type (PTC), 86; follicular adenoma (FA), 21; follicular carcinoma (FC), 35; medullary carcinoma (MC), 3; undifferentiated carcinoma (UC), 5; and Hurthle cell neoplasm (HN), 4. Using immunohistochemical staining, COX-2 expression was detected in 62 (72.1%) PTC specimens, 5 (23.8%) FA specimens, 10 (28.6%) FC specimens, 0 (0.0%) MC specimens, 1 (20.0%) UC specimen, and 3 (75%) HN specimens. iNOS expression was detected in 66 (76.7%) PTC specimens, 4 (19.0%) FA specimens, 13 (37.1%) FC specimens, 0 (0.0%) MC specimens, 3 (60.0%) UC specimens, and 4 (100%) HN specimens. The results showed that COX-2 and iNOS were frequently expressed in the PTC and HN specimens, and iNOS was more frequently overexpressed in the FC specimens than in the FA specimens. In PTC, COX-2 and iNOS were significantly overexpressed in patients over 45 yr of age (p=0.029, p=0.041), and iNOS expression was increased in patients with a large primary tumor (p=0.028). These results suggest that the upregulation of COX-2 and iNOS may contribute to the tumor progression of thyroid gland, particularly in PTC and HN, and iNOS may play an adjuvant role during the tumor progression of FC.
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PMID:Cyclooxygenase-2 and inducible nitric oxide synthase expression in thyroid neoplasms and their clinicopathological correlation. 1717 88

We examined the effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the lung cancer cell lines PC-9, LA-1 and A549. In addition, we examined if the effects of the cytokines on the cell lines are mediated by activation of cyclooxygenase (COX)-2. The three cell lines did not constitutively produce either G-CSF or GM-CSF. G-CSF did not influence cell growth in the three cell lines, while GM-CSF increased cell growth in the A549 and LA-1 lines. G-CSF and GM-CSF dose-dependently decreased cell death in the three cell lines. RT-PCR demonstrated GM-CSF receptor expression in the three lung cancer cell lines, whereas the G-CSF receptor exists only in the PC-9 line. We suggest that G-CSF might rescue the tumor cells from cytotoxicity due to serum deprivation through cellular pathways independent of the G-CSF receptor. G-CSF and GM-CSF increased cyclooxygenase-2 (COX-2) expression in PC-9 and LA-1 cells whereas they decreased COX-2 expression in A549 cells. The COX-2 inhibitor NS-398 increased cell death in PC-9 and LA-1 cells, whereas it decreased cell death in A549 cells. PC-9 and LA-1 clones transfected with sense G-CSF- or GM-CSF showed an increase in COX-2 expression, while COX-2 expression was decreased in transfected A549 clones. COX-2 expression was increased in anti-sense G-CSF- and GM-CSF-transfected A549 clones. Thus, although COX-2 activation seems to induce different biological behavior depending on the cell type, we propose that G-CSF and GM-CSF might accelerate tumor progression by directly regulating COX-2 expression, independently of an autocrine mechanism.
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PMID:Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on lung cancer: roles of cyclooxygenase-2. 1734 42


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