UMLS:C0178874 - FACTA Search

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)

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.
...
PMID:Signal transduction cross-talk during colorectal tumorigenesis. 1699 21

Inhibition of prostaglandin E(2) (PGE(2)) and cyclooxygenase (COX)-2 by nonsteroidal anti-inflammatory drugs reduces the progression of colon cancer. Inhibition of aldose reductase (AR; EC. 1.1.1.21.) by sorbinil or by antisense ablation prevented fibroblast growth factor-induced and platelet-derived growth factor-induced up-regulation of PGE(2) synthesis in human colon cancer cells, Caco-2. AR besides reducing aldo-sugars efficiently reduces toxic lipid aldehydes and their conjugates with glutathione. Inhibition of AR prevented growth factor-induced COX-2 activity, protein, and mRNA and significantly decreased activation of nuclear factor-kappaB and protein kinase C (PKC) and phosphorylation of PKC-beta2 as well as progression of Caco-2 cell growth but had no effect on COX-1 activity. Cell cycle analysis suggests that inhibition of AR prevents growth factor-induced proliferation of Caco-2 cells at S phase. Treatment of Caco-2 cells with the most abundant and toxic lipid aldehyde 4-hydroxy-trans-2-nonenal (HNE) or its glutathione-conjugate [glutathionyl-HNE (GS-HNE)] or AR-catalyzed product of GS-HNE, glutathionyl-1,4-dihydroxynonane (GS-DHN), resulted in increased COX-2 expression and PGE(2) production. Inhibition of AR prevented HNE- or GS-HNE-induced but not GS-DHN-induced up-regulation of COX-2 and PGE(2). More importantly, in vivo studies showed that administration of AR-small interfering RNA (siRNA), but not control siRNA, to nude mice bearing SW480 human colon adenocarcinoma cells completely arrested tumor progression. Collectively, these observations suggest that AR is an obligatory mediator of growth factor-induced up-regulation of COX-2, PGE(2), and growth of Caco-2 cells, indicating that inhibition of AR may be a novel therapeutic approach in preventing the progression of colon cancer.
...
PMID:Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin E2 production in human colon cancer cells. 1701 29

Preclinical and clinical studies have clearly shown a benefit of nonsteroidal anti-inflammatory drug (NSAID) use in reducing cancer risk. However, the adverse gastrointestinal and cardiovascular side effects associated with NSAIDs and COX-2 selective inhibitors (coxibs) have provoked more scrutiny of the precise role of specific downstream mediators in the prostaglandin (PG) signaling cascade. NSAIDs and coxibs inhibit PG biosynthesis. One of the PGs produced at high levels in the tumor microenvironment is PGE(2), which is thought to play a major role in cancer progression. Thus, a better understanding of PGE(2) signaling could enable identification of novel and safer therapeutic targets downstream of the cyclooxygenase enzymes. We review the emerging molecular mechanisms by which COX-2-derived PGE(2) is involved in cancer progression and delineate potential opportunities for development of novel pharmacologic approaches utilizing this pathway.
...
PMID:NSAIDs and cancer prevention: targets downstream of COX-2. 1710 May 52

We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using methylation-specific multiplex ligation-dependent probe amplification, and TP53 and CDH1 mutation analysis where relevant. The primary tumors and xenografts were histologically comparable and shared expression of 11 of 14 immunohistochemical markers (E-cadherin, beta-catenin, COX-2, p53, p16, TFF1, cyclin E, MLH1, SMAD4, p27, KLK3, CASR, CHFR, and DAPK1). Gains of CASR, DAPK1, and KLK3--not yet described in gastric cancer--were present in the primary tumors, xenografts, and cell lines. The most prominent losses occurred at CDKN2A (p16), CDKN2B (p15), CDKN1B (p27/KIP1), and ATM. Except for ATM, these losses were found only in the cell line or xenograft, suggesting an association with tumor progression. However, examination of p16 and p27 in 174 gastric cancers using tissue microarrays revealed no significant correlation with tumor stage or lymph node status. Further losses and hypermethylation were detected for MLH1, CHFR, RASSF1, and ESR, and were also seen in primary tumors. Loss of CHFR expression correlated significantly with the diffuse phenotype. Interestingly, we found the highest rate of methylation in primary tumors which gave rise to cell lines. In addition, both cell lines harbored mutations in CDH1, encoding E-cadherin. Xenografts and gastric cancer cell lines remain an invaluable research tool in the uncovering of the multistep progression of cancer. The frequent gains, losses, and hypermethylation reported in this study indicate that the involved genes or chromosomal regions may be relevant to gastric carcinogenesis.
...
PMID:Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis. 1737 10

Ocimum sp. is a traditionally used medicinal herb, which shows anti-oxidant, anti-carcinogenic, radio-protective and free radical scavenging properties. So far no detailed studies have been reported on its effects on human cancers. Thus, we analyzed its effects on human breast cancer utilizing in vitro and in vivo methodologies. Aqueous extracts were prepared from the mature leaves of Ocimum gratissimum (OG) cultivated devoid of pesticides. Tumor progression and angiogenesis related processes like chemotaxis, proliferation, apoptosis, 3D growth and morphogenesis, angiogenesis and tumor growth were studied in the presence or absence of the extract, and in some experiments a comparison was made with purified commercially available eugenol, apigenin and ursolic acid. Aqueous OG leaf extract inhibits proliferation, migration, anchorage independent growth, 3D growth and morphogenesis and induction of COX-2 protein in breast cancer cells. A comparative analysis with eugenol, apigenin and ursolic acid showed that the inhibitory effects on chemotaxis and 3D morphogenesis of breast cancer cells were specific to OG extract. In addition, OG extracts reduced tumor size and neoangiogenesis in a MCF10 DCIS.com xenograft model of human DCIS. This is the first detailed report showing that OG leaf extract may be of value as a breast cancer preventive and therapeutic agent and might be considered as additional additive in the arsenal of components aimed at combating breast cancer progression and metastasis.
...
PMID:Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum gratissimum. 1743 70

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that aberrant induction of COX-2 and up-regulation of the prostaglandin cascade play a significant role in carcinogenesis, and reciprocally, blockade of the process has strong potential for cancer prevention and therapy. Supporting evidence includes the following: [1] expression of constitutive COX-2-catalyzed prostaglandin biosynthesis is induced by most cancer-causing agents including tobacco smoke and its components (polycylic aromatic amines, heterocyclic amines, nitrosamines), essential polyunsaturated fatty acids (unconjugated linoleic acid), mitogens, growth factors, proinflammatory cytokines, microbial agents, tumor promoters, and other epigenetic factors, [2] COX-2 expression is a characteristic feature of all premalignant neoplasms, [3] COX-2 expression is a characteristic feature of all malignant neoplasms, and expression intensifies with stage at detection and cancer progression and metastasis, [4] all essential features of carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis, and immunosuppression) are linked to COX-2-driven prostaglandin (PGE-2) biosynthesis, [5] animal studies show that COX-2 up-regulation (in the absence of genetic mutations) is sufficient to stimulate the transformation of normal cells to invasive cancer and metastatic disease, [6] non-selective COX-2 inhibitors, such as aspirin and ibuprofen, reduce the risk of human cancer and precancerous lesions, and [7] selective COX-2 inhibitors, such as celecoxib, reduce the risk of human cancer and precancerous lesions at all anatomic sites thus far investigated. Results confirming that COX-2 blockade is effective for both cancer prevention and therapy have been tempered by observations that some COX2 inhibitors pose a risk to the cardiovascular system, and more studies are needed in order to determine if certain of these drugs can be taken at dosages that prevent cancer without increasing cardiovascular risk. It is emphasized that the "inflammogenesis model of cancer" is not mutually exclusive and may in fact be synergistic with the accumulation of somatic mutations in tumor suppressor genes and oncogenes or epigenetic factors in the development of cancer.
...
PMID:Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. 1761 47

In response to various growth factors, hormones or cytokines, arachidonic acid can be mobilized from phospholipids pools and converted to bioactive eicosanoids through cyclooxygenase (COX), lipoxygenase (LOX) or P-450 epoxygenase pathway. The COX pathway generates five major prostanoids (prostaglandin D(2), prostaglandin E(2), prostaglandin F(2)alpha, prostaglandin I(2) and thromboxane A(2)) that play important roles in diverse biological processes. Studies suggest that different prostanoids and their own synthase can play distinct roles in tumor progression and cancer metastasis. COX-2 and PGE(2) synthase have been most well documented in the regulation of various aspects of tumor progression and metastasis. PGE(2), for example, can stimulate angiogenesis or other signaling pathways by binding to its receptors termed EPs. Therefore, targeting downstream prostanoids may provide a new avenue to impede tumor progression. In this review, aberrant expression and functions of several prostanoid synthetic enzymes in cancer will be discussed. The possible regulation of tumor progression by prostaglandins and their receptors will also be discussed.
...
PMID:Cyclooxygenases, prostanoids, and tumor progression. 1776 71

Cyclooxygenase-2 (Cox-2) is a key enzyme in the conversion of arachidonic acid to prostaglandins that has been shown to have a particular importance in the progression of several malignancies including nasopharyngeal carcinoma (NPC). In the current report, we designed a case-controlled study to evaluate the susceptibility and prognostic implications of the functional -765 G > C genetic variation in NPC. A PCR and restriction fragment length polymorphism analysis was used to determine the polymorphism in a Tunisian population of patients with NPC (n = 180) and in healthy control subjects (n = 169). A higher risk for NPC was observed for carriers of COX-2 -765 C allele (OR = 1.76; P = 0.01). This association remains significant after adjustments for age and sex (OR = 1.89; P = 0.008). Regarding prognostic indicators, a significant association was found between -765 C allele carriers and the presence of lymph node metastasis (OR = 2.28; P = 0.01), as well as, with tumor stage (OR = 2.73; P = 0.03). This is the first report on the studies of COX-2 SNPs in NPC and our data suggest that this genetic variant may play a role in mediating susceptibility to NPC, as well as, in neoplastic progression, a finding which further supports the involvement of COX-2 in NPC etiology.
...
PMID:PTGS2 (COX-2) -765 G > C functional promoter polymorphism and its association with risk and lymph node metastasis in nasopharyngeal carcinoma. 1796 76

Oncogenic Ras mutations are early genetic events in colorectal cancer that induce cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) biosynthesis. PGE(2), a downstream product of COX-2, promotes cancer progression by modulating proliferation, apoptosis and angiogenesis. 15-hydroxyprostaglandin dehydrogenase (PGDH) degrades PGE(2) and is down-regulated in colorectal cancer, suggesting that PGDH plays a role in regulating PGE(2) levels and that PGDH over-expression could attenuate Ras-mediated tumorigenesis. Lentiviral transduction was used to express GFP (18.GFP), K-Ras(V12) (18.K-Ras(V12)), PGDH (18.PGDH) or both K-Ras(V12) and PGDH (18.K-Ras(V12).PGDH) in nontumorigenic rat intestinal epithelial (IEC-18) cells. 18.K-Ras(V12) cells exhibited increased phosphorylation of MAP kinases and CREB, proliferation rates, COX-2 and microsomal prostaglandin E synthase (mPGES)-1 expression and PGE(2) and PGI(2) levels. 18.PGDH and 18.K-Ras(V12).PGDH cells had 10(4)-fold increases in PGDH activity with decreased PGE(2) and PGI(2) levels, COX-2 and mPGES-1 expression and proliferation rates. 18.GFP, 18.PGDH, and 18.K-Ras(V12).PGDH cells were unable to grow in soft agar media whereas 18.K-Ras(V12) cells exhibited anchorage-independent cell growth. Xenografts of implanted 18.K-Ras(V12) cells in nu/nu mice produced rapid (2 wk) tumors with uniform antibody staining for COX-2 and mPGES-1 throughout the tumor and elevated PGE(2) levels. Xenografts of 18.K-Ras(V12).PGDH cells exhibited delayed (8 wk) tumor formation with negligible COX-2 and mPGES-1 expression and significantly decreased PGE(2) levels. 18.K-Ras(V12).PGDH tumors had decreased staining of the proliferative marker, Ki-67, and a significant increase in apoptosis in the central region of the tumor. Based on these data, we conclude that PGDH expression suppresses K-Ras(V12)-mediated tumorigenesis in intestinal epithelial cells.
...
PMID:15-Hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice. 1805 8

APC-germline mutation creates predisposition for intestinal tumorigenesis. APCMin/+ mice, developing tumors preferentially in the small intestine and only minimally in the colon, were fed pectin-enriched diets (10% galacturonan; degree of methoxylation=37.0 and 70.4%) or standard diet. Pectins used in the present study do not inhibit intestinal tumorigenesis and rather accelerate it in APCMin/+ mice. Both pectins exhibited prebiotic effects associated with high fermentative formation of acetate but producing low butyrate. The differences of the short-chain fatty acid concentrations between cecum and colon and those between colon and feces were larger than expected and increased with cancer progression, indicating an inhibition of butyrate absorption. Pectins transported more bile acids toward the colon than the standard diet and caused a higher generation of secondary bile acids despite lower pH values. Overexpression of COX-2 resulted in lower antioxidative capacity, thus promoting cancer. Apoptosis increased in hyperplasia but decreased in late adenomas. When biological modular design principles are taken into consideration, it can be expected that pectin also reinforces colorectal tumorigenesis of patients suffering from APC gene defects.
...
PMID:Pectin does not inhibit intestinal carcinogenesis in APC-deficient Min/+ mice. 1819 30

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>