UMLS:C0699790 - FACTA Search

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

To study the mechanisms that control epithelial commitment and differentiation we have used undifferentiated HT-29 colon cancer cells and a subpopulation of mucus secreting cells obtained by selection of HT-29 cells in 10-6 M methotrexate (M6 cells) as experimental models. We isolated cDNAs encoding transcripts overexpressed in early confluent M6 cells regarding steady-state levels in HT-29 cells by subtractive hybridisation. Fifty-one cDNA clones, corresponding to 34 independent transcripts, were isolated, partially sequenced by their 5' end, and classified into four groups according to their identity: transcripts that included a repeated sequence of the Alu family (10 clones, among them those encoding ribonucleoprotein RNP-L and E-cadherin), transcripts encoded by the mitochondrial genome (nine clones), transcripts encoding components of the protein synthesis machinery (23 clones, including the human ribosomal protein L38 not previously cloned in humans) and nine additional cDNAs that could not be classified in the previous groups. These last included ferritin, cytokeratin 18, translationally controlled human tumour protein (TCHTP), mt-aldehyde dehydrogenase, as well as unknown transcripts (three clones), and the human homologues of the molecular motor kinesin KIF3B and of the ser/thr protein kinase EMK1. Spot dot and Northern blot analyses showed that ser/thr protein kinase EMK1 was differentially expressed in M6 cells when compared with parental HT-29 cells. Steady-state levels of EMK1 were higher in proliferating, preconfluent, M6 and HT-29 cells than in 2 days post confluence (dpc) and 8dpc M6 and HT-29 cells. Transcripts that included an Alu repeat were also shown to be differentially expressed and accumulated in differentiating M6 cells when analysed by Northern blot. The significance of the transcripts cloned is discussed in the context of the commitment and differentiation of the M6 cells to the mucus secreting lineage of epithelial cells.
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PMID:Expressed sequence tag (EST) phenotyping of HT-29 cells: cloning of ser/thr protein kinase EMK1, kinesin KIF3B, and of transcripts that include Alu repeated elements. 1039 37

The p120ctn protein (formerly p120CAS) is an armadillo family member that associates directly with the cytoplasmic tail of E-cadherin and participates in the junctional complex responsible for cell-cell adhesion. Since reduced cell-cell adhesion is associated with metastasis in colorectal cancer and other neoplasms, we hypothesize that reduced expression of p120ctn may be related to metastasis in colorectal tumors. Here we describe a study of p120ctn expression in 44 primary human colorectal adenocarcinomas. As detected by immunohistochemical methods, we find altered p120ctn staining patterns in 86% of the cases. Regional complete loss of expression is seen in 18% of the cases, and it correlates with high stage disease and nodal metastasis as well as decreased survival. Although this is a preliminary study, it suggests that downregulation of p120ctn in colon cancer may be associated with metastasis and poor clinical outcome.
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PMID:Loss of p120ctn in human colorectal cancer predicts metastasis and poor survival. 1039 74

beta-Catenin mediates the interaction of E-cadherin with alpha-catenin and the actin cytoskeleton. Recent evidence indicates that when the tumor suppressor gene APC is inactivated, beta-catenin can translocate to the nucleus, where it acts as a transcriptional regulator. Because APC is inactivated in most colorectal cancers, beta-catenin nuclear localization would be expected in these tumors. In a study of adhesion molecule expression in frozen colorectal cancer tissues, we were surprised by failure to detect nuclear beta-catenin. Here we compared the reactivity of an anti-beta-catenin monoclonal antibody with 11 colorectal cancers using immunohistochemistry on sections of frozen or paraffin-embedded samples. beta-Catenin was never detected in the nuclei of normal or tumor cells in frozen tissue sections. By contrast, in 8/11 cases it was detected in the nuclei of tumor cells but not of normal cells in paraffin-embedded tissue sections. These results were confirmed with an independent rabbit polyclonal anti-beta-catenin serum. We also examined beta-catenin distribution in SW480 colon cancer cells, in which its nuclear accumulation has been reported. As in tissues, nuclear beta-catenin was detected in paraffin-embedded but not in frozen samples. These findings are relevant because of the increasing interest in the study of beta-catenin in tumors, based on its dual role in cell adhesion and transcriptional regulation.
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PMID:Nuclear beta-catenin in colorectal tumors: to freeze or not to freeze? Colon Cancer Team at IMAS. 1042 93

Tumour cell metastatic potential is significantly enhanced following treatment with HGF/SF, the ligand for the c-met receptor tyrosine kinase. Following c-met activation in tumour cells, phosphorylation of beta-catenin occurs, together with loss of intercellular adhesion and a gain in the motile and invasive nature of the cell. In this study we show that c-met is co-localised with beta-catenin and E-cadherin at regions of cell-cell contact in human colon cancer (HRT18 and HT115) and two breast cancer (MCF7 and MDA MB 231) cell lines. Immunoprecipitation studies demonstrated an association between c-met and members of the cadherin adhesion complex in these epithelial tumour cells, along with the membrane tyrosine protein phophatase, PTPmu. We conclude that the HGF/SF receptor, c-met, together with members of the cadherin/catenin cell-cell adhesion system and PTPmu, may form part of a protein complex in E-cadherin positive tumour cells that acts to regulate intercellular adhesion following HGF/SF stimulation.
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PMID:Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells. 1042 98

E-cadherin is a cell-cell adhesion molecule expressed predominantly by epithelial cells. Reduction or loss of E-cadherin immunoreactivity has been associated with tumour progression in many epithelial cancers, including bladder carcinomas. The fibroblast growth factor receptor 2b (FGFR2b) recognized specifically by FGF7 is expressed only by epithelial cells. Recently, decreased expression of FGFR2b protein and mRNA was found to be associated with tumour progression in bladder carcinomas. The purpose of this investigation was to look for a possible relationship between E-cadherin and FGFR2b expression in bladder carcinomas. As decreased E-cadherin immunoreactivity was found to correlate directly with decreased expression at the mRNA level, the possible relationship between E-cadherin and FGFR2b was investigated at the mRNA level using semi-quantitative RT - PCR in 92 transitional cell carcinomas (TCCs) and four lymph node metastases. All tumours with low E-cadherin expression had low expression of FGFR2b, whereas tumours with low FGFR2b mRNA could express any level of E-cadherin mRNA. The same observation was equally valid for bladder and colon cancer cell lines suggesting that, besides bladder tumours, this relationship could apply to other carcinomas types. These results suggest that a relationship exists between the transcription of the E-cadherin and FGFR2b genes preventing high expression of FGFR2b where expression of E-cadherin is low. We suggest that reduced expression of FGFR2b in conjunction with decreased expression of E-cadherin may contribute to the aggressive behaviour attributable to high grade TCCs.
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PMID:Relationship between E-cadherin and fibroblast growth factor receptor 2b expression in bladder carcinomas. 1052 52

Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.
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PMID:beta-catenin signaling and cancer. 1058 Sep 87

beta-catenin, a component of the E-cadherin-catenin cell adhesion complex, also plays a separate intracellular signalling role, interacting with APC protein. Intracellular accumulation of beta-catenin is common in colorectal neoplasia. beta-catenin abnormalities are associated with poor survival in gastric cancer, but previous studies do not differentiate between membrane-associated and intracellular beta-catenin. In this study we aimed to determine which type of expression abnormalities for E-cadherin, beta-catenin and alpha-catenin correlate with clinico-pathological features and survival in gastric cancer. Immunoperoxidase staining of paraffin-embedded sections from 40 gastric cancers was performed for E-cadherin, alpha- and beta-catenins using microwave unmasking and an avidin-biotin technique. Clinical data were obtained from case records and cancer registry records. Reduced membranous expression of beta-catenin occurred in 10/12 (83%) diffuse and 8/28 (29%) intestinal tumours (P= 0.0014), and was associated with poor differentiation (P= 0.0015) and short survival (P= 0.032), but not with age, sex, tumour size or nodal status. Nuclear expression of beta-catenin was uncommon; cytoplasmic expression was observed in 13/40 cases (33%) but did not correlate with histology, tumour grade or survival. Reduced E-cadherin membrane expression was associated with lymph node metastasis (P= 0.02). Neither E-cadherin or alpha-catenin expression correlated with survival. Reduced membranous expression of beta-catenin predicts poor prognosis in gastric cancer, whilst ectopic intracellular expression is relatively rare. The apparent differences in beta-catenin expression from those found in colon cancer merit further study.
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PMID:Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer. 1060 38

Cell-to-cell adhesion, an important event in differentiation, is impaired during advanced stages of tumorigenesis. In this study, we examined the possible regulation of cell-adhesion proteins by the differentiation agent butyrate in LS174T and HM7 cells, two types of human colon cancer cells that differ in their ability to produce mucin and colonize the liver of experimental animals. The more aggressive, high-mucin-producing cell line (HM7), a clone selected from LS174T cells, showed a scattered and undifferentiated ultramorphological appearance and low basal alkaline phosphatase activity; the proteins beta-catenin and E-cadherin, as detected by immunostaining, were expressed in the cells' nuclei. All of these properties were significantly less pronounced in the less aggressive, low-mucin-producing LS174T cells. In both cell lines, butyrate treatment enhanced cell-to-cell interaction, alkaline phosphate activity, translocation of beta-catenin and E-cadherin from the nuclei to the membrane junctions, and transcription and translation of the 120-kDa E-cadherin isoform, but not of its 100-kDa isoform. Analysis of possible mechanisms of E-cadherin up-regulation revealed that butyrate induces the release of nuclear proteins from the E-cadherin promoter sequence, reducing transcription repression. We suggest that butyrate activates E-cadherin transcription through translocation of nuclear transcription factors bearing specific repressor activity. We surmise that abrogation of nuclear 100-kDa E-cadherin and beta-catenin expression following butyrate treatment is related to the control of E-cadherin gene transcription.
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PMID:Butyrate regulates E-cadherin transcription, isoform expression and intracellular position in colon cancer cells. 1063 89

A gene related to cell differentiation was identified by differential display as a candidate suppressor of metastases in colon cancer. This gene, with a full-length cDNA of 3 kb, is expressed in normal colon and primary colon cancer tissues and cell lines but not in their metastatic counterparts. A GenBank search found that it is identical to a recently cloned gene, differentiation-related gene-1 (Drg-1), isolated from differentiated HT-29 colon cancer cells. Stable transfection of the SW620 metastatic colon cancer cell line with Drg-1 cDNA induced morphological changes consistent with differentiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine (100 nM), an inhibitor of DNA methylation. Functional studies revealed that overexpression of Drg-1 in metastatic colon cancer cells reduced in vitro invasion through Matrigel and suppressed in vivo liver metastases in nude mice. We propose that Drg-1 suppresses colon cancer metastasis by inducing colon cancer cell differentiation and partially reversing the metastatic phenotype.
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PMID:Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. 1067 63

Cancer is a genetic disease. The unstable genome of cancer cells causes tumour progression through multiple alterations in suppressor and promoter genes, leading to loss of homeostatic and gain of oncogenic functions. Invasion is the critical step in the acquisition of malignancy. It implicates a continuous molecular conversation of the cancer cells with other cells and with the extracellular matrix in which adhesion molecules are crucial. One of these, E-cadherin, is discussed in the present review. E-cadherin is a transmembrane glycoprotein that forms a complex with cytoplasmic proteins, termed catenins because they link E-cadherin to the actin cytoskeleton. E-cadherin/catenin-mediated intercellular adhesion and communication is mainly homophylic homotypic. There is compelling evidence from experiments in vitro as well as in vivo to accept that the E-cadherin/catenin complex acts as an invasion suppressor. The mechanism of this action is not only through cell-cell adhesion but also through transduction of signals to the cell's motility system. In the replication error positive human colon cancer cell line HCT-8, the alpha E-catenin gene CTNNA1 is an invasion suppressor gene. Here, the transition from the non-invasive to the invasive state was prevented by introduction into the unstable non-invasive cells of either an extra CTNNA1 or a wild type hMSH6 mismatch repair gene. beta-catenin also participates at a complex which comprises the adenomatous polyposis cancer protein APC. In colorectal cancer, mutation of either APC or beta-catenin is oncogenic. Downregulation of the E-cadherin/catenin complex may occur in several ways amongst which are gene mutations, methylation of 5'CpG dinucleotides within the promotor region of E-cadherin, tyrosine phosphorylation of beta-catenin, cell surface expression of proteoglycans sterically hindering E-cadherin and proteolytic release of fragments from the extracellular part of E-cadherin. Upregulation of the E-cadherin/catenin complex has been realized with a series of agents, some of which can be used therapeutically. In most human gastrointestinal cancers the E-cadherin/catenin or related complexes are disturbed and this underscores their pivotal role in the progression of these tumours. Mutations of the E-cadherin gene, including germline mutations, occur in diffuse gastric carcinoma, CpG methylation around the promotor region of E-cadherin in hepatocellular carcinomas and mutations of the APC tumour suppressor gene or in the beta-catenin oncogene in most colorectal cancers. The literature agrees about the disturbance of immunohistochemical patterns of E-cadherin and catenin expression in gastrointestinal cancers. Conflicting opinions do, however, exist about the prognostic value of such immunohistochemical aberrations. We doubt that immunohistochemistry of E-cadherin or catenins add prognostic value to the already used histological grading systems. In our opinion the major benefit from understanding of the E-cadherin/catenin-mediated pathways of invasion will be the development of new anti-invasive treatment strategies.
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PMID:The role of the E-cadherin/catenin complex in gastrointestinal cancer. 1069 69

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