Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor/scatter factor (HGF/SF) is a protein growth factor whose pleiotropic effects on epithelial cells include the stimulation of motility, mitosis and tubulogenesis. These responses are mediated by the cell surface tyrosine kinase receptor c-met. Because both the cytokine and receptor are found in the gastrointestinal tract, we have studied the effects of HGF/SF on transformed gut epithelial cells which express c-met. Here we describe the response of a new transformed human jejunal epithelioid cell line (HIE-7) to HGF/SF. Morphologically HIE-7 cells are immature. Their epithelial lineage was confirmed by reactivity with the epithelial specific antibodies AE1/AE3, Cam 5.2, Ber-EP4 and anti-EMA and is consistent with their expression of c-met mRNA and protein. In addition, electron microscopic analysis revealed the presence of primitive junctions and rudimentary microvilli, but features of polarization were absent. When grown on reconstituted basement membranes, HIE-7 cells formed closely associated multicellular cord-like structures adjacent to acellular spaces. However, the cells did not mature structurally, form lumen-like structures or express disaccharidase mRNA, even in the presence of recombinant HGF (rHGF). On the other hand, rHGF induced HIE-7 cells to scatter and stimulated their rapid migration in a modified wound assay. To determine whether the mitogenic effect caused by rHGF is associated with HIE-7 cell invasiveness across reconstituted basement membranes, a Boyden chamber chemoinvasion assay was performed. rHGF stimulated a 10-fold increase in the number of HIE-7 cells that crossed the basement membrane barrier, while only stimulating a small increase in chemotaxis across a collagen IV matrix, suggesting that the cytokine activates matrix penetration by these cells. rHGF also stimulated the invasion of basement membranes by an undifferentiated rat intestinal cell line (IEC-6) and by two human colon cancer cell lines which are poorly differentiated (DLD-1 and SW 948). In contrast, two moderately well differentiated colon cancer cell lines (Caco-2 and HT-29) did not manifest an invasive response when exposed to rHGF. These results suggest that HGF/SF may play a significant role in the invasive behavior of anaplastic and poorly differentiated gut epithelial tumors.
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PMID:Hepatocyte growth factor stimulates invasion across reconstituted basement membranes by a new human small intestinal cell line. 830 28

We previously demonstrated that cyclooxygenase-2 (COX-2) was predominantly expressed in macrophages of sporadic human colonic adenomas; however, the role of COX-2-expressing cells during colon carcinogenesis has not yet been elucidated. In the present study, we showed the effect of PGE, on vascular endothelial growth factor (VEGF) production by PMA-differentiated U937 cells, a human macrophage model (H-Mac), and by human colon cancer cells T84. PGE1 dramatically induced VEGF production by H-Mac, but not that by T84. PGE1 significantly increased intracellular cAMP formation by H-Mac, but only modestly increased that by T84. 8-bromo-cAMP and cholera toxin also increased VEGF production by H-Mac. In contrast, neither of these agents modulated VEGF production by T84. EP2 and EP4 (PGE specific receptors) mRNA was expressed in both cells. PG dramatically increased VEGF production by activated macrophages, but not by cancer cells, through a specific PGE receptor-mediated process. These findings suggest that PGs produced by COX-2-expressing macrophages induce VEGF production by macrophages, but not by cancer cells, in an autocrine fashion.
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PMID:Effect of prostaglandin E1 on vascular endothelial growth factor production by human macrophages and colon cancer cells. 1096 22

To establish a novel molecular diagnostic method of detecting circulating tumor cells (CTCs) LS174T colon cancer cells were serially diluted with normal blood. Additional peripheral blood samples were collected from 25 patients with colorectal carcinoma. Mononuclear cells (MNCs) were collected, equally divided into four parts, and then cancer cells were enriched by four methods: method A, nonimmunobead method; method B, negative immunobead method: CD45 immunomagnetic beads were used to deplete the leukocytes; method C, positive immunobead method: Ber-EP4 immunomagnetic beads were used to enrich cancer cells; method D, negative-and-positive immunobead method: CD45 immunomagnetic beads were first used to deplete the leukocytes from MNC and then Ber-EP4 immunomagnetic beads were used to enrich cancer cells. Finally, real-time quantitative RT-PCR was used to monitor mRNA expression of beta2-mircoglobulin (beta2M) and carcinoembryonic antigen (CEA). The relative CEA mRNA values were corrected with reference to beta2M mRNA, to CEA mRNA/beta2M mRNA ratios according to a CEA mRNA external standards prepared with tenfold serial dilutions (1-10(4) IS174T cells) of cDNA and beta2M mRNA external standards prepared with tenfold serial dilutions (10(2)-10(7) leukocytes) of cDNA. In recovery experiments a significant correlation between the number of cancer cells and CEA mRNA expression was found when CD45 or Ber-EP4 immunomagnetic beads were used alone. A highly significant correlation was found when CD45 and Ber-EP4 immunomagnetic beads were used successively. The sensitivity of method D was one cancer cell per milliliter of blood. Circulating cancer cells were detected in 19 of 25 patients with colorectal cancers. The relative CEA mRNA value obtained by method D was the smallest. The positive detection rate of circulating cancer cells in patients at Dukes' B, C, and D stages were 25.0% (1/4), 83.3% (10/12), and 88.9% (8/9). Combinative use of immunomagnetic isolation followed by real-time RT-PCR is a useful technique to detect circulating tumor cells in patients with colorectal carcinomas. Applying negative and positive immunomagnetic beads successively yields the highest correlation with amount of tumor cells.
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PMID:Combined use of positive and negative immunomagnetic isolation followed by real-time RT-PCR for detection of the circulating tumor cells in patients with colorectal cancers. 1549 93

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

Mice deficient in the G-protein alpha subunit G(i)alpha(2) spontaneously develop colitis and colon cancer. IL-11 is a pleiotropic cytokine known to protect the intestinal epithelium from injury in animal models of colitis and is produced by subepithelial myofibroblasts in response to inflammatory mediators including TGF-beta, IL-1beta, and PGE(2). Arachidonic acid release and subsequent PGE(2) production is significantly decreased in the colonic mucosa of G(i)alpha(2)-/- mice, and we hypothesized that this would affect mucosal IL-11 production. Mucosal levels of IL-11 were found to be significantly decreased in G(i)alpha(2)-/- mice despite the presence of mild colitis. Primary cultures of G(i)alpha(2)-/- intestinal and colonic myofibroblasts (IMF and CMF, respectively) produced less basal and TGF-beta or IL-1beta-stimulated IL-11 mRNA and protein than wild-type cells. Inhibitors of ERK or p38 MAPK activation dose dependently inhibited IMF and CMF IL-11 production in response to TGF-beta stimulation, whereas 16,16 dimethyl-PGE(2) and prostanoid receptor subtype-selective agonists induced IL-11 production. Treatment of animals with the EP4-specific agonist ONO-AE1-329 resulted in enhanced mucosal levels of IL-11, and increased IL-11 production by ex vivo cultured CMF. Modulation of cAMP levels produced diverging results, with enhancement of TGF-beta-induced IL-11 release in IMF pretreated with 8-Br-cAMP and inhibition in cells treated either with pertussis toxin or the PKA inhibitor H-89. These data suggest a physiological role for prostaglandins, MAPK signaling, and cAMP signaling for the production of myofibroblast-derived IL-11 in the mouse intestinal mucosa.
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PMID:Decreased MAPK- and PGE2-dependent IL-11 production in Gialpha2-/- colonic myofibroblasts. 1733 78

Nonsteroidal anti-inflammatory drugs (NSAIDs) can decrease the risk of colorectal cancer; however, it has not been established if this effect is solely through their ability to inhibit cyclooxygenase (COX). In this study the effects of indomethacin, a potent NSAID and nonselective COX inhibitor, was examined in LS174T human colon cancer cells. These cells were found to express EP2 prostanoid receptors, but not the EP1, EP3 or EP4 subtypes. Pretreatment of LS174T cells with indomethacin produced a complete inhibition of prostaglandin E(2) (PGE(2)) stimulated cyclic AMP (cAMP) formation in a dose dependent manner with an IC(50) of 21 microM. Interestingly, the inhibition of PGE(2)-stimulated cAMP formation by indomethacin was accompanied by a decrease in EP2 mRNA expression and by a decrease in the whole cell specific binding of [(3)H]PGE(2). Thus, treatment of LS174T cells with indomethacin causes a down regulation of EP2 prostanoid receptors expression that may be independent of COX inhibition.
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PMID:Indomethacin decreases EP2 prostanoid receptor expression in colon cancer cells. 1755 11

Accumulating evidence indicates that elevated levels of prostaglandin E(2) (PGE(2)) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE(2) exerts its effects through four G-protein-coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE(2) to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE(2)-induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE(2) induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE(2) treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant-negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE(2) driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE(2) in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer.
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PMID:The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells. 1763 Dec 91

PGE2 plays a critical role in colorectal carcinogenesis. We have previously shown that COX-2 expression and PGE2 synthesis are mediated by IGF-II/IGF-I receptor signaling in the Caco-2 cell line and that the pathway of phosphatidylinositol 3-kinase (PI3K)/Akt protects the cell from apoptosis. In the present study, we demonstrate that PGE2 has the ability to increase Ras and PI3K association and decrease the level of apoptosis in the same experimental system. The effect of PGE2 on PI3K/Ras association is dependent on the activation of EP4 receptor, the increase of cAMP levels, and the activation of PKA. In fact, treatment of cells with the PKA inhibitor H89 decreases the association of Ras and PI3K and Ras-associated PI3K activity. PKA inhibitor H89 is able to decrease threonine phosphorylation of Akt and to increase serine phosphorylation of Akt by p38 MAPK and counteracts the cytoprotective effect induced by PGE2. In addition, PGE2 is able to activate p38 MAPK and the inhibition of p38 MAPK, with SB203580 specific inhibitor or with dominant negative MKK6 kinase, is able to revert the apoptotic effect of H89 and serine phosphorylation of Akt. The effect of PGE2 on Caco-2 cell survival through PKA activation is mediated and regulated by the balance of threonine/serine phosphorylation of Akt by p38 kinase and PI3K. In conclusion, our data elucidate a novel mechanism for regulation of colon cancer cell survival and provide evidences for new combinatory treatments of colon cancer.
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PMID:PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation. 1764 Sep 74

Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by prostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P=0.032) and inversely with node positivity (P=0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P=0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression.
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PMID:Prostanoid receptor EP1 expression in breast cancer. 1790 15

Little is yet known about the origin and protective mechanism of free nucleic acids in plasma. We investigated the possibility of these free nucleic acids being particle associated. Plasma samples from colon cancer patients and cell culture media were subjected to various antibody incubations, ultracentrifugation, and RNA extraction protocols for total RNA, epithelial RNA, and mRNA. Flow cytometry using a Ber-EP4 antibody and confocal laser microscopy after staining with propidium iodide were also performed. mRNA levels of the LISCH7 and SDHA genes were determined in cells and in culture media. Ber-EP4 antibody and polystyrene beads coated with oligo dT sequences were employed. We observed that, after incubation, total RNA and mRNA were always detected after membrane digestion, and that epithelial RNA was detected before this procedure. In ultracentrifugation, mRNA was caught in the supernatant only if a former lysis mediated or in the pellet if there was no previous digestion. Flow cytometry determinations showed that antibody-coated microbeads keep acellular structures bearing epithelial antigens apart. Confocal laser microscopy made 1- to 2-microm-diameter particles perceptible in the vicinity of magnetic polystyrene beads. Relevant differences were observed between mRNA of cells and culture media, as there was a considerable difference in LISCH7 mRNA levels between HT29 and IMR90 cell co-cultures and their culture media. Our results support the view that extracellular RNA found in plasma from cancer patients circulates in association with or is protected in a multiparticle complex, and that an active release mechanism by tumor cells may be a possible origin.
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PMID:Extracellular plasma RNA from colon cancer patients is confined in a vesicle-like structure and is mRNA-enriched. 1845 45


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