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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of gastrins and their receptors in the pathogenesis of colon cancer has been discussed for many years but it still remains unresolved. Although fluorouracil (FU) remains to be reference chemotherapy for colon cancer, its efficacy is unsatisfactory. Recently, we have shown a synergistic effect of proglumide (a non-selective blocker of cholecystokinin-gastrin receptors) applied together with FU, on the proliferation and apoptosis of transplantable Colon 38 cancer cells in vivo. The aim of this study was to examine direct effects of proglumide (10(-5)-10(-10) M) applied either alone or together with FU (0.25, 2.5 and 25 microg/ml) on the proliferation of murine Colon 38 cancer cells in vitro. Cell proliferation was assessed by the modified colorimetric Mosmann method. Proglumide inhibited the proliferation of Colon 38 cells at the concentrations of 10(-6), 10(-8) and 10(-10) M. FU inhibited the proliferation of cancer cells in all studied concentrations, exerting the most profound antiproliferative effect at the concentrations of 2.5 and 25 microg/ml. Thus, the former concentration was chosen to study its interactions with proglumide. Proglumide applied together with FU exerted a synergistic effect on the inhibition of proliferation of Colon 38 cells at 10(-8), 10(-9), 10(-10) M concentrations. The most profound inhibitory effect was observed in the group incubated with FU and 10(-10) M of proglumide. The obtained results indicate a possibility of new therapeutic options for colon cancer, but further studies are needed to elucidate, if the synergistic effect of FU and proglumide occurs also in the colon cancer in humans.
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PMID:The combined effects of proglumide and fluorouracil on the growth of murine Colon 38 cancer cells in vitro. 1682 Dec 14

We and others have reported the presence of novel progastrin (PG)/gastrin receptors on normal and cancerous intestinal cells. We had earlier reported the presence of 33-36 kDa gastrin-binding proteins on cellular membranes of colon cancer cells. The goal of the current study was to identify the protein(s) in the 33-36 kDa band, and analyse its functional significance. A carbodiimide crosslinker was used for crosslinking radio-labeled gastrins to membrane proteins from gastrin/PG responsive cell lines. Native membrane proteins, crosslinked to the ligand, were solubulized and enriched by >1000-fold, and analysed by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry. The peptide masses were researched against the NCBInr database using the ProFound search engine. Annexin II (ANX II) was identified, and confirmed by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. As HCT-116 cells express autocrine PG, the in situ association of PG with ANX II was demonstrated in pulldown assays. Direct binding of PG with ANX II was confirmed in an in vitro binding assay. In order to confirm a functional importance of these observations, sense and anti-sense (AS) ANX II RNA-expressing clones of intestinal epithelial (IEC-18) and human colon cancer (HCT-116) cell lines were generated. AS clones demonstrated a significant loss in the growth response to exogenous (IEC-18) and autocrine (HCT-116) PG. We have thus discovered that membrane-associated ANX II binds PG/gastrins, and partially mediates growth factor effects of the peptides.
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PMID:Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells. 1683 41

Focal adhesion kinase (FAK) is suggested to be intimately involved in the progression of malignancies. Our previous research has demonstrated that activation of cholecystokinin-2 receptor (CCK2R) by gastrin stimulates a rapid activation of FAK pathway in human colon cancer cells. The purpose of this study is to determine the role of CCK2R and FAK in the progression of colon cancer. In this study, matched tissue samples of primary colon cancer and adjacent normal colon mucosa from the same patient were collected from 45 patients with colon cancer undergoing surgical resection. The gastrin expression was detected using reverse transcription polymerase chain reaction (RT-PCR). The CCK2R expression was examined by in situ hybridization and RT-PCR. The expression of FAK and phosphorylated FAK at tyrosine 397 (phospho-FAK) were detected using immunohistochemistry and immunoblotting. Colo320 and SW787, 2 colon cancer cell lines with or without CCK2R expression, were recruited in this study. Antisense oligonucleotide of FAK was used to block the expression of FAK. Invasiveness and motility of colon cancer cells were detected by Boyden chamber. In this series, enhanced expression of gastrin, CCK2R, FAK and phospho-FAK were observed in colon cancer tissues. CCK2R expression correlated with expression of phospho-FAK. Coexpression of CCK2R and phospho-FAK associated with invasion and lymph node metastasis. Increased invasion and motility was induced by gastrin in Colo320 cells. Overexpression of CCK2R by stable transfection of CCK2R plasmid amplified this increase and incubation with 1 microM L-365,260, a specific CCK2R antagonist, completely inhibited the effect of gastrin. FAK antisense largely blocked the increase of invasion and motility in Colo320 cells. Our data represent the evidence for the CCK2R regulating invasion and motility of colon cancer cells, and support a role of CCK2R in the progression of colon cancer. FAK play a critical role in this CCK2R-mediated effect.
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PMID:Enhanced expression of cholecystokinin-2 receptor promotes the progression of colon cancer through activation of focal adhesion kinase. 1699 32

Colon carcinogenesis is a multistep process that involves deletions, mutations, and changes in expression of genes that regulate growth, differentiation, and apoptosis. Hyperproliferation can initiate dysplastic growth, resulting in accumulation of genetic defects and progression of colon cancer. Although genetic instability, because of inheritance of specific genetic defects, plays a dominant role in familial cancers, in the majority of sporadic cancers hyperproliferation is likely to play a permissive role in initiation and progression of the disease. Thus factors that regulate growth, differentiation, and apoptosis are likely to play an important role in colon carcinogenesis. Autocrine gastrins, insulin-like growth factor-II, transforming growth factor-alpha, and endocrine gastrins have been implicated in the tumorigenic potential of colon cancer cells. In this article we focus on the role of endocrine and autocrine gastrins in colon cancer and review recent advances that suggest a role of processing intermediates of gastrin in colon carcinogenesis.
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PMID:Role of autocrine and endocrine gastrin-like peptides in colonic carcinogenesis. 1702 20

The role of the gastrin peptide hormones (G17, G34) and their precursors (progastrins, PG; gly-extended gastrin, G-gly), in gastrointestinal (GI) cancers has been extensively reviewed in recent years [W. Rengifo-Cam, P. Singh, Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment, Curr. Pharm. Des. 10 (19) (2004) 2345-2358; M. Dufresne, C. Seva, D. Fourmy, Cholecystokinin and gastrin receptors, Physiol. Rev. 86 (3) (2006) 805-847; A. Ferrand, T.C. Wang, Gastrin and cancer: a review, Cancer Lett. 238 (1) (2006) 15-29]. A possible important role of progastrin peptides in colon carcinogenesis has become evident from experiments with transgenic mouse models [W. Rengifo-Cam, P. Singh, (2004); A. Ferrand, T.C. Wang, (2006)]. It is now known that growth stimulatory and co-carcinogenic effects of gastrin/PG peptides are mediated by both proliferative and anti-apoptotic effects of the peptides on target cells [H. Wu, G.N. Rao, B. Dai, P. Singh, Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3, J. Biol. Chem. 275 (42) (2000) 32491-32498; H. Wu, A. Owlia, P. Singh, Precursor peptide progastrin(1-80) reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP, Am. J. Physiol. Gastrointest. Liver Physiol. 285 (6) (2003) G1097-G1110]. Several receptor subtypes have been described that mediate growth effects of gastrin peptides [W. Rengifo-Cam, P. Singh (2004); M. Dufresne, C. Seva, D. Fourmy, (2006)]. Recently, we identified Annexin II as a high affinity binding protein for gastrin/PG peptides [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798]. Importantly, the expression of Annexin II was required for mediating growth stimulatory effects of gastrin and PG peptides on intestinal epithelial and colon cancer cells [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798], suggesting that Annexin-II may represent the elusive novel receptor for gastrin/PG peptides. The importance of this finding in relation to the structure and function of Annexin-II, especially in GI cancers, is described below. Since this surprising finding represents a new front in our understanding of the mechanisms involved in mediating growth effects of gastrin/PG peptides in GI cancers, our current understanding of the role of Annexin-II in proliferation and metastasis of cancer cells is additionally reviewed.
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PMID:Role of Annexin-II in GI cancers: interaction with gastrins/progastrins. 1718 24

Many studies have pointed out a possible role of gut peptides, including gastrin and ghrelin, in the pathogenesis and natural history of gastrointestinal malignancies, one of the most common death cause in the Western world. The objective of this work is to check gastrin and ghrelin serum levels in patients with colorectal cancer according to tumour's location, stage, Helicobacter pylori infection and BMI, in order to understand the two peptides' behaviour through the tumour's natural history and evaluate their assay's use in research and clinical practice. Twenty-nine subjects affected by colorectal cancer and 50 healthy controls were studied. Circulating gastrin and ghrelin levels and H. pylori serum antibodies were assessed by radioimmunologic assay and ELISA method. Gastrin and ghrelin serum levels were respectively slightly higher and significantly lower in colon cancer patients than in controls. Gastrin levels were higher in patients carrying left colon cancer and H. pylori infection while ghrelin levels were lower in both these groups. Both hormones' serum levels decreased from tumour earlier to later stages. Significant differences persisted in the correlation between BMI and ghrelin levels in controls but not in patients. Additional studies are necessary to ascertain the significance of gastrin and ghrelin opposite behaviour in colon cancer probably linked with interferences in endocrine pathways involving other gut peptides in this compromised condition.
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PMID:Circulating gastrin and ghrelin levels in patients with colorectal cancer: correlation with tumour stage, Helicobacter pylori infection and BMI. 1725 85

Cyclooxygenase-2, the inducible enzyme of arachidonic acid metabolism and prostaglandin synthesis, is over expressed in colorectal cancer. Inhibition of COX-1/-2 by non-steroidal anti-inflammatory drugs is associated with a decreased risk for these malignancies, whereas high serum gastrin levels elevate this risk. As gastrin exhibits trophical effects on colonic epithelium we sought to explore whether it is capable to induce COX-2 expression in a human colon cancer cell line. The aim of this study is the description of the gastrin evoked effects on the transcriptional activity of the COX-2 gene in colorectal cancer cells and the identification of regulatory promoter elements. Reporter gene assays were performed with the gastrin-stimulated human colorectal cancer cell-line Colo-320, which was stable transfected with the human cholecystokinin-B/gastrin receptor cDNA and COX-2-promoter-luciferase constructs containing different segments of the 5'-region of the COX-2 gene or with mutated promoter constructs. Transcription factors were characterized with electrophoretic mobility shift assays. Gastrin-dependent induction of COX-2 mRNA was shown using "real-time" PCR. Resulting elevated Prostaglandin E2-levels were measured using ELISA. Gastrin stimulated the PGE2-generation and COX-2-mRNA expression in human Colo-320-B cells potently, obviously by transactivating the COX-2-promoter using a region between - 68 bp and + 70 bp. Further examinations identified a CRE-E-box element between - 56 bp and - 48 bp mediating the gastrin-effects on the COX-2 gene. Transcription factors binding to this promoter element were USF-1 und -2. These results show the necessity to perform succeeding studies, which could describe possible mechanisms in which gastrin and COX-2 contribute to the induction of colorectal carcinomas.
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PMID:An upstream CRE-E-box element is essential for gastrin-dependent activation of the cyclooxygenase-2 gene in human colon cancer cells. 1760 53

Addressing the puzzling role of amidated gastrin(17) (G17) and the gastrin/CCKB/CCK2 receptor in colorectal carcinogenesis, we analysed potential candidate genes involved in G17-dependent NF-kappaB inhibition and apoptosis. The colorectal carcinoma cell line Colo320 overexpressing the wild-type CCK2 receptor (Colo320wt) underwent G17-induced apoptosis along with suppressed NF-kappaB activation and decreased expression of the antiapoptotic NF-kappaB target genes cIAP1 and cIAP2, whereas G17 was without effect on Colo320 cells expressing a CCK2 receptor bearing a loss of function mutation (Colo320mut). Gene microarray analysis revealed an elevated expression of the stress response gene IEX-1 in G17-treated Colo320wt but not Colo320mut cells. Quantitative real-time PCR and conventional RT-PCR confirmed this G17-dependent increase of IEX-1 expression in Colo320wt cells. If these cells were subjected to IEX-1 knockdown by small interfering RNA transfection, the apoptosis-inducing effect of G17 was abolished. Moreover, tumor necrosis factor alpha (TNFalpha)- or 5-FU-induced apoptosis that is greatly enhanced by G17 treatment in Colo320wt cells was prevented if IEX-1 expression was repressed. Under these conditions of blocked IEX-1 expression, the NF-kappaB activity remained unaffected by G17, in particular in Colo320wt cells co-treated with TNFalpha and also the suppressive effect of G17 on cIAP1 and cIAP2 expression was not observed anymore if IEX-1 expression was blocked. Conversely, IEX-1 overexpression in Colo320mut cells caused an increase of basal and TNFalpha- or 5-FU-induced apoptosis, an effect not further triggered by G17 treatment. Using a xenograft tumor model in severe combined immune deficiency mice, we could show that experimental systemic hypergastrinemia induced by the administration of omeprazole led to enhanced apoptosis as well as to a marked increase of IEX-1 expression in Colo320wt tumors, but not in Colo320mut tumors. These observations indicate that the proapoptotic effect of G17 on human colon cancer cells expressing the wild-type CCK2 receptor is mediated by IEX-1, which modulates NF-kappaB-dependent antiapoptotic protection and thereby exerts tumor-suppressive potential.
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PMID:The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition. 1770 4

The expression of the human cholecystokinin-2/gastrin receptor (CCK-2R) has been widely reported in human colorectal cancers. Recently, a splice variant of the CCK-2R retaining intron 4 (CCK-2i4svR) has been cloned from human colorectal cancers and postulated to exhibit constitutive activity. But its role in mediating carcinogenic effects of mature-amidated gastrin in colorectal cancers has not been fully explored. The purpose of the present study was to determine whether the activation of CCK-2i4svR by gastrin transactivates the COX-2 promoter in human colon cancer cells and in COS-7 cells. In this study, Colo320 cells and COS-7 cells were transfected with the human CCK-2R wild type (CCK-2wtR) (COS-7WT, Colo320WT) and the human CCK-2i4svR (COS-7SV, Colo320SV) cDNA. After stimulation with gastrin-17 (G-17), transactivation of the COX-2 promoter was determined by luciferase reporter gene assay. 5'deletions of the COX-2 promoter were transfected into Colo320 cells to narrow down the minimally required regulatory element. Induction of COX-2 expression was further explored at the mRNA level using real time RT-PCR. The effects of CCK-2i4svR activation on phosphorylation of ERK1/2, p38(MAPK) and JNK were examined by using immunoblotting. Prostaglandin E(2) (PGE(2)) secretion was measured by ELISA. Our results showed that gastrin transactivates the COX-2 promoter in both Colo320 cells and COS-7 cells expressing the CCK-2i4svR cDNA. Inhibition of p38(MAPK) pathway using specific inhibitor significantly blocked the gastrin-induced COX-2 transactivation. Gastrin time-dependently increased COX-2 mRNA expression, the peak mRNA levels appeared at 10 h after stimulation. PGE(2) secretion from gastrin-treated cells increased significantly 8 h after stimulation. Treatment with gastrin also stimulated PGE(2) secretion in the Colo320 cells expressing CCK-2i4svR. In conclusion, the CCK-2i4svR mediates transactivation of the COX-2 promoter and MAPK pathway is involved in this process.
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PMID:The CCK-2/gastrin splice variant receptor retaining intron 4 transactivates the COX-2 promoter in vitro. 1793 21

Peroxisome proliferator-activated receptor gamma (PPAR gamma) are members of the largest nuclear hormone receptor family of transcription factors (1). PPAR gamma (PPARgamma) plays an important role in adipogenesis, control of sensitivity to insulin, inflammation and atherosclerosis but recent studies also suggest that PPARgamma is involved in cell cycle withdrawal. PPARgamma can promote cell differentiation, exert an antiproliferative action and inhibit angiogenesis (2, 3). However, there are studies showing that activation of PPARgamma promotes the development of colon cancer (4). These data are in sharp contrast with studies that attribute anticancer effects to PPARgamma in gastrointestinal malignancies. Probably, the action of PPARgamma on cell cycle and proliferation depends on the cell type and presence of other stimuli that predispose cells to cancer development. Amidated and non-amidated gastrins may play an important role in the proliferation and carcinogenesis of GI cancers. It is known that gastrin peptides activate phosphorylation of Protein Kinase B (PKB/Akt) and anti-apoptotic signalling but there is little known about the link between gastrins and PPARgamma receptors in relation to apoptosis.
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PMID:Transcriptional upregulation of gastrin in response to peroxisome proliferator-activated receptor gamma agonist triggers cell survival pathways. 1819 88


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