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)

Preclinical and clinical studies in our laboratory have suggested that prostaglandin (PG) E2 is involved in anorexia and cachexia development, although the role of COX pathways on the pathogenesis of cancer cachexia remains to be clarified. Expressions of PGE (EP1, EP2, EP3alpha,beta,gamma and EP4) and PGI (IP) receptors in the central nervous system (brain cortex, hypothalamus and brain stem), in peripheral (liver, white adipose tissue and skeletal muscle) and tumor tissue from MCG-101-bearing mice with and without indomethacin treatment were investigated by RT-PCR and immunohistochemistry. Expression of EP1 in the liver and EP4 receptor in white adipose tissue were upregulated and responded to indomethacin treatment, while downregulated expression of EP3 in skeletal muscle from tumor-bearing mice was unresponsive to indomethacin treatment despite improved carcass weight. Expression of EP and IP receptors in brain and tumor tissue from tumor-bearing mice were neither related nor responsive to systemic PGE2 levels including increased IL-1beta, IL-6 and TNF-alpha host activities. The expression IP receptor in CNS, peripheral tissue and tumor tissue was unchanged by cachexia development. Our results suggest that transcription of EP receptors in liver, fat and skeletal muscle tissue may be a control level for host metabolic alterations during tumor progression, while overall EP and IP receptor expression in CNS did not indicate an important control level for appetite regulation in MCG 101-bearing mice despite prostanoid related anorexia.
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PMID:Prostaglandin E and prostacyclin receptor expression in tumor and host tissues from MCG 101-bearing mice: a model with prostanoid-related cachexia. 1570 39

Cyclooxygenase-2 and prostaglandin E(2) (PGE(2)) levels are increased in colorectal cancers and a subset of adenomas. PGE(2) signaling through the EP4 receptor has previously been associated with colorectal tumorigenesis. However, changes in EP4 expression during adenoma to carcinoma progression have not been investigated, neither has whether levels of EP4 influence important markers of malignant potential, such as anchorage-independent growth or the tumors growth response to PGE(2). We report using immunohistochemistry that in vivo EP4 receptor protein expression was increased in colorectal cancers (100%) as well as adenomas (36%) when compared with normal colonic epithelium. EP4 expression was also higher in colorectal carcinoma compared with adenoma cell lines and increased with in vitro models of tumor progression. Adenoma (PC/AA/C1 and RG/C2) and carcinoma cell lines (HT29) were growth stimulated by PGE(2) up to 0.5 micromol/L. However, although carcinoma and transformed adenoma (PC/AA/C1SB10C, a transformed derivative of PC/AA/C1) cells remain stimulated by higher doses of PGE(2) (10 micromol/L), the adenoma cell lines were inhibited. Interestingly, enforced expression of EP4 in the adenoma cell line, RG/C2, resulted in stimulation of growth by 10 micromol/L PGE(2) and promoted anchorage-independent growth. Both in vivo and in vitro data from this study suggest that increased EP4 receptor expression is important during colorectal carcinogenesis. We propose that high levels of PGE(2) in a tumor microenvironment would select for cells with increased EP4 expression, and that the EP4 receptor may therefore represent an important target for colorectal cancer prevention and treatment.
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PMID:Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence. 1654 Jun 60

The prostaglandin E2 receptor, EP4 receptor (EP4R), plays an important role in the development of transitional cell carcinoma of the upper urinary tract (TCC-UUT). However, the clinical significance of other EP receptors (EP1R-3R) is not clear. Furthermore, the pathological function of EP receptors in such patients is not understood. In the present study, we examined the expression of EP1R-3R in 101 TCC-UUT tissues by immunohistochemistry. Furthermore, we defined the relationship between cyclooxygenase (COX)-2 and EP receptor expression, proliferation index (PI), microvessel density (MVD), and expression of metalloproteinase-2 (MMP-2), urokinase-type plasminogen activator (uPA), and exon v6 containing CD44 isoform (CD44 v6) by multivariate analysis. The expression of EP1R, EP2R, and EP3R was positive in 20 (19.8%), 26 (25.7%), and 14 (13.9%) tumor samples, respectively. Expression of these receptors was not associated with pathological findings or survival. COX-2 and EP4R were independently associated with MVD and MMP-2, and uPA or PI and MMP-2, respectively. Other EP receptors were not influenced by any factors. Our results suggest that EP1R-3R play a minimal role in cancer progression in patients with TCC-UUT. On the other hand, EP4R regulates tumor progression via cancer cell proliferation and MMP-2, distinct from COX-2.
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PMID:Pathological function of prostaglandin E2 receptors in transitional cell carcinoma of the upper urinary tract. 1660 7

Copy number gains and high-level amplifications of the short arm of chromosome 5 are frequently observed in soft tissue sarcomas. To identify genes from this region possibly involved in tumor progression, we analyzed 34 soft tissue sarcomas (10 pleomorphic and 8 dedifferentiated liposarcomas, 6 malignant fibrous histiocytomas, and 10 malignant peripheral nerve sheath tumors (MPNST)) using a DNA microarray including 418 BAC clones representing 99% of chromosome arm 5p. In seven tumors, distinct high-level amplifications were identified affecting four different subregions. From these regions, genes TERT, TRIO, SKP2, FBXO32, NKD2, SLC6A3, IRX2, POLS, FYB, PTGER4, and FGF10 were selected for detailed quantitative expression analysis (RQ-PCR) based on their potential tumorigenic function. Of these, TRIO, coding for a guanidine nucleotide exchange factor, was consistently overexpressed in all cases, while IRX2 and NKD2, both involved in the regulation of developmental processes via the WNT pathway, showed a characteristic expression only in MPNSTs. Detailed nonparametric multidimensional scaling analysis further showed that the expression of TRIO, IRX2, and NKD2 strongly correlated with the gene copy number. In conclusion, we found TRIO, IRX2, and NKD2 frequently affected by high-level amplifications as well as up-regulated in a gene-dosage dependent manner. Thus, these genes represent candidate targets of 5p amplifications in soft tissue sarcomas and might play a crucial role during the progression of this disease.
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PMID:Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas. 1675 83

Colorectal carcinoma (CRC) is the second leading cause of cancer-related death in the United States in the general population (men and women combined). Epidemiologic data obtained over the last several decades shows convincing evidence for the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in the reduction of risk of CRC through the inhibition of cycloxygenase (COX). Recent research has also demonstrated that prostaglandin E2 (PGE2), a predominant product of COX, plays a critical role in tumorigenesis of CRCs through its guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), EP2, and EP4. Molecular analysis of CRC and its precursor lesions have shown that mutation of Adenomatous Polyposis Coli (APC), a gene involved in the wingless type signaling pathway, is an early event during the neoplastic progression in the majority of sporadic CRCs. The fundamental questions are: why is wild type APC so important in adult colorectal tissues in preventing this tumorigenesis, and what are the mechanisms by which NSAIDs prevent colorectal tumorigenesis? We reviewed the recent literature concerning the PGE2-GPCR signaling pathway and the APC-beta-catenin (wingless type) pathway in CRC cells and propose a unifying schema regarding the tumorigenesis of CRC. Colorectal epithelia are continuously exposed to various extracellular agonists (including low levels of PGE2). The binding of these agonists to their corresponding GPCRs leads to formation of activated Galphas, which in turn activates beta-catenin. In normal colorectal epithelia, wild type APC blocks the Galphas-induced activation of beta-catenin, and therefore maintains homeostasis and prevents tumorigenesis. In contrast, in the absence of functional APC, continuous formation of activated Galphas by the binding of various extracellular agonists to their receptors leads to the activation and nuclear accumulation of beta-catenin. This elevated nuclear beta-catenin in turn increases transcription of many genes (COX-2, C-myc, Cyclin D1, vascular endothelial growth factor, T cell factor, etc.) involved in tumorigenesis. Increased transcription of COX-2 also leads to excessive production of PGE2 that in turn forms a stimulatory loop with many biologic functions (proliferation, migration, invasion, angiogenesis, and inhibition of apoptosis), which may result in the development of CRC. Because NSAIDs inhibit COX and decrease the production of PGE2, interruption of the cycle helps prevent colorectal tumorigenesis.
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PMID:Signal transduction cross-talk during colorectal tumorigenesis. 1699 21

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

Prostaglandin E2 (PGE2) can stimulate tumor progression by both direct and indirect mechanisms. However, its influence on cell proliferation is still unclear. The present study characterized expression of subtypes of PGE2 receptors in oral squamous cell carcinomas, while also investigating the effects of EP3 and EP4 selective antagonists on oral carcinoma cell lines. EP1, EP2, EP3 and EP4 receptor mRNAs were detected in 4, 5, 10 and 10 of 11 surgical specimens respectively. Application of an EP3 antagonist (ONO-AE3-240) strongly inhibited cell growth in COX-2 and PGE2 high expression cells (Ca9-22) but not in COX-2 and PGE2 low expression cells (HSC4). The antagonist also reduced the production of endogenous PGE2 and induced G0/G1 phase cell arrest. Addition of exogenous PGE2 only partly abrogated the growth inhibition, indicating that the anti-proliferative effect via EP3 receptor signaling was not only due to PGE2-dependent but also PGE2-independent mechanisms. In contrast, an EP4 antagonist (ONO-AE3-208) did not inhibit growth in either of the cancer cell lines. In summary, PGE2 receptor EP3 signaling probably contributes to development of oral carcinomas and use of EP3 antagonist may be a new therapeutic strategy for head and neck cancer.
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PMID:Expression of prostaglandin E2 receptors in oral squamous cell carcinomas and growth inhibitory effects of an EP3 selective antagonist, ONO-AE3-240. 1921 90

Most ovarian cancers arise from the mesothelial surface lining of the ovaries or from invaginations of this lining into the superficial ovarian cortex that form cortical inclusion cysts. Thus, these cysts are thought to be precursor lesions of ovarian carcinoma. Epithelial-mesenchymal transition, which is a transcriptional program for inducing maintenance of the mesenchymal phenotype, acts in tumor progression and metastasis. Little is known about the mechanisms involved in mesenchymal-epithelial transition (MET). We aimed to characterize the human ovarian surface epithelium (OSE) and inclusion cysts by immunohistochemical analysis to examine whether MET occurs during inclusion cyst formation in the OSE. We used specimens from 9 endometrial cancer patients who had undergone hysterectomy and bilateral salpingo-oophorectomy. Immunohistochemical analysis was performed in 10 normal ovaries containing 92 inclusion cysts and in 4 normal tubes to examine the expression of antigen markers including calretinin, podoplanin, D2-40, thrombomodulin, HBME-1, vimentin, EMA, WT1, CA125, MOC31, TAG-72, Ber-EP4 and E-cadherin. The positive staining rates for mesothelial markers in normal OSE were 100% (10/10) for calretinin, 80% (8/10) for podoplanin, 80% (8/10) for D2-40, 70% (7/10) for thrombomodulin, 100% (10/10) for HBME-1, 100% (10/10) for vimentin. The positive staining rates for epithelial markers in tubal epithelium were 100% (4/4) for HBME-1, 100% (4/4) for vimentin, 100% (4/4) for EMA, 75% (3/4) for TAG-72, 100% (4/4) for Ber-EP4. Inclusion cysts showed positive staining for both markers with an incidence of 51% (47/92) for HBME-1, 44% (41/92) for vimentin, 65% (60/92) for TAG-72, 88% (81/92) for Ber-EP4. The OSE showed the characteristics of both mesenchymal and epithelium cells. In contrast, inclusion cysts gained epithelial characteristics, but lost mesenchymal characteristics. These findings support that MET occurs during the inclusion cyst formation from OSE.
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PMID:Mesenchymal to epithelial transition in the human ovarian surface epithelium focusing on inclusion cysts. 1936 Feb 96

Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. However, despite these encouraging outcomes, the appearance of unwanted side effects remains a major hurdle for the general application of COX-2 inhibitors as effective cancer drugs. Hence, a better understanding of the molecular signals downstream of COX-2 is needed for the elucidation of drug targets that may improve cancer therapy. Here, we show that the COX-2 product prostaglandin E(2) (PGE(2)) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE(2) enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE(2)-mediated lung cancer cell migration. PGE(2) affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression. Proximal EP4 effectors include heterotrimeric Gs and betaArrestin proteins. Knockdown of betaArrestin1 expression with shRNA significantly impaired the PGE(2)-induced c-Src activation and cell migration. Together, these results support the idea that increased expression of the COX-2 product PGE(2) in the lung tumor microenvironment may initiate a mitogenic signaling cascade composed of EP4, betaArrestin1, and c-Src which mediates cancer cell migration. Selective targeting of EP4 with a ligand antagonist may provide an efficient approach to better manage patients with advanced lung cancer.
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PMID:Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. 2035 98

Previous studies indicate that COX-2 and prostaglandin E(2) (PGE(2)) receptor subtypes are involved in intestinal carcinogenesis and activation of downstream pathways. In this report, we try to understand the association of PGE(2) receptor and K-ras cellular mechanism during the development of colorectal cancer. We collected 21 colorectal cancer patients and compared the protein expression of tumor tissues and normal mucosa tissues by using immunoblot. Furthermore, we transferred empty vector and pcDNA-K-ras into Ras-HT29 colon cancer cells. Result showed that phosphorylation of Akt and EP(1)/EP(4) were over-expressed in the colorectal tumor tissue. K-ras induces HT29 cells proliferation through the expressions of COX-2, EP1/EP4, pAkt, GSK3beta and increases Tcf transcriptional factor activation. Additionally, Ras protein was suppressed when treated with EP(4) inhibitor in Ras-HT29 cell. In cell cycle assay, K-ras mutation causing cell cycle S phase was prolonged with an increase in the G2/M phase ratio. In conclusion, we suggested that Ras overexpression leads to cell proliferation through activating Ras/PI3K/GSK3beta/EP(4) PGE(2) receptor signals and caused a feedback regulation of Ras by EP4 in colorectal tumor progression.
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PMID:EP4 upregulation of Ras signaling and feedback regulation of Ras in human colon tissues and cancer cells. 2057 79


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