UMLS:C0033036 - FACTA Search

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Query: UMLS:C0033036 (APC)
10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Due to its increasing incidence, esophageal adenocarcinoma and its precursor lesions have received increasing attention in recent years. The histopathologic steps in the process of malignant progression in Barrett's esophagus are well described and include the following: (a) metaplasia of the normal esophageal squamous epithelium to a specialized intestinal glandular epithelium, (b) development of dysplasia (classified histologically as low and high grade), and (c) development of adenocarcinoma characterized by invasive and metastatic potential. Intestinal metaplasia can be identified by the presence of goblet cells, the detection of which can be aided by finding mucin stained by Alcian blue at low pH. Despite this well-characterized sequence, the timing of the development of dysplasia and the subsequent transition to carcinoma and the risk of development of carcinoma in low- and high-grade dysplasia are not precisely known. In addition, there are problems in the identification of dysplasia, including sampling error and interobserver discrepancies among pathologists. A better understanding of the mechanisms of these events would allow early identification and elimination of high-risk lesions before adenocarcinoma with its attendant poor prognosis were able to develop. In order to better understand this process and to potentially identify early markers of malignant transformation, a variety of molecular studies have been carried out in recent years on adenocarcinoma and its precursor lesions in Barrett's esophagus. On the phenotypic level, increased expression and changes in pattern of expression of proliferation marker (Mib-1) Ki-67 antigen, overexpression of p53 protein, overexpression of growth factors such as epidermal growth factor (EGF), c-erbB2, and transforming growth factor (TGF)-a, decreased and abnormal expression of the cell adhesion molecule E-cadherin, and, in carcinomas, increased expression of serine proteases have all been described. A new area of interest is the family of rab proteins, which play an important role in maintaining cell polarity in the gastrointestinal tract. Increased expression of one of these proteins, rab11, has been described in low-grade, but not high-grade dysplasia. In cytogenetic studies, an increased S-phase fraction, followed by an increased tetraploid (4N) fraction and then aneuploidy, has been described. So far, the specific genes which have been most thoroughly investigated have been p53, APC, p16, and the sites of probable tumor suppressor genes, including 3p (FHIT), 13q, and 18q. With only a few exceptions (i.e., rab11 expression, and possibly mutations of FHIT), the numerous molecular abnormalities which have been described occur late in malignant progression, which means that the best marker which presently exists to identify high-risk lesions in Barrett's esophagus is the histologic identification of dysplasia in endoscopic biopsies, especially high-grade dysplasia. We are presently beginning studies using laser microdissection and competitive genomic hybridization (CGH), which could help to identify new chromosomal areas that might contain genes that are crucial in the early phases of malignant progression in Barrett's esophagus. In the future, identification of such early molecular events which predispose to carcinoma development will allow more precise and earlier risk assessment for individual patients, therefore, enabling more effective therapy.
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PMID:Malignant progression in Barrett's esophagus: pathology and molecular biology. 1069 36

Wnt/beta-catenin signaling is frequently activated in cancer cells by stabilizing mutations of beta-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of beta-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the beta-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3beta phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of beta-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear beta-catenin immunostaining in undifferentiated cells. Membranous beta-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that beta-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of beta-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.
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PMID:Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas. 1069 19

beta-catenin regulates cadherin-mediated cell-cell adhesion and also functions as a signaling molecule. In this study, we examined the expression pattern of E-cadherin, alpha-catenin and beta-catenin in 22 cases of esophageal squamous-cell carcinoma by Western-blot analysis. Expression of E-cadherin, alpha-catenin and beta-catenin was lower in carcinomas than in normal esophageal mucosa in 4 cases (18.2%) for E-cadherin, 6 cases (27.3%) for alpha-catenin and 9 cases (40.9%) for beta-catenin. Expression of beta-catenin was not always correlated with that of E-cadherin. Over-expression of beta-catenin was observed in 3 cases (13.6%). Of 3 cases that presented with over-expression of beta-catenin, 2 showed cytoplasmic staining by immunohistochemistry. Nuclear localization of beta-catenin was observed in one case that had higher beta-catenin level in tumor tissue (1.4-fold higher than normal mucosa). The genomic DNA sequences of the beta-catenin and the APC gene were analyzed. No mutation of the beta-catenin gene was observed in any cases. Silent mutation of the APC gene was found in all the cases that showed over-expression or nuclear localization of the beta-catenin protein. These results indicate that alterations of the cadherin-catenin complex may play an important role in a sub-set of esophageal carcinogenesis. Furthermore, it is suggested that beta-catenin over-expression is not caused by genetic alteration of either the beta-catenin or the APC gene.
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PMID:Alteration of beta-catenin expression in esophageal squamous-cell carcinoma. 1070 91

Like sporadic colorectal cancers, ulcerative colitis (UC)-related cancers are thought to evolve through a multistep progression pathway. The genomic alterations important in sporadic colorectal carcinogenesis are well characterized, with loss of APC function being a frequent and early event. However, the genomic alterations in UC-related carcinogenesis are yet unclear and the role of APC is controversial. In this study genomic alterations in UC-related cancers, dysplasias and nondysplasias were assessed by comparative genomic hybridization (CGH). Alterations of the APC/beta-catenin pathway were evaluated by immunohistochemistry. 32 cases of UC-related cancers (14 with synchronous dysplasias and nondysplasias) and 42 sporadic cancers were matched by UICC stage. CGH was performed using DOP-PCR amplification after microdissection. Expression of beta-catenin, E-cadherin and APC were detected by immunohistochemistry in paraffin sections. Chromosomal alterations were present in 90% of the sporadic and 94% of the UC-related cancers. 86% of the UC-related dysplasias and 36% of the nondysplasias showed changes by CGH. Chromosome 5q was lost in 56% of UC-related cancers and 36% of the dysplasias but in only 26% of the sporadic cancers. Other frequent alterations in both cancer groups were loss of 18q, 8p, 17p, and gain of 8q and 20q. Immunohistochemistry showed a decrease of membranous and an increase of cytoplasmic expression of E-cadherin and beta-catenin in UC-related and sporadic cancers. APC expression was significantly decreased in both tumor types. Clonal chromosomal alterations occur early in UC-related tumor progression. UC-related and sporadic cancers share a set of common clonal abnormalities. The frequent loss of 5q and the altered expression of APC, beta-catenin, and E-cadherin proteins in UC-related cancers indicate a critical role of the APC/beta-catenin pathway in UC-related carcinogenesis.
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PMID:[Molecular carcinogenesis in ulcerative colitis-associated and sporadic colorectal carcinoma--differences and similarities]. 1071 3

Colorectal carcinoma is a major cause of death throughout the Western world. It is increasingly recognized that any reduction in mortality must be achieved through the detection and removal of early and precancerous lesions. The primary attention for such a preventive strategy has been the polypoid adenoma and surveillance studies have shown a significant reduction in the incidence of carcinoma through systematic polypectomy of suspicious lesions. A potential problem with such a program, however, is raised by reports from Japan that some carcinomas seem to arise without a precursor polypoid adenoma, that is de novo. Although the histopathologic findings in such reports seem to clearly support this idea, this concept is not widely accepted in the Western world. We undertook a series of immunohistochemical (p53, bcl-2, Mib-1, E-cadherin, CD44, Stromelysin-3), and microsatellite analysis studies (on 17p (p53), 18q (DCC), 5q (APC), 8p, 2p and 1p), on groups of de novo and ex adenoma carcinomas in order to see if differences between the two groups of lesions exist. The results of these studies demonstrate that de novo carcinomas share several phenotypic and genotypic features with ex adenoma carcinoma (similar CD44 in the carcinomas, similar rates of LOH at APC and DCC loci), but have significantly higher rates of LOH at 17p, p53 over-expression and ST-3 expression indicating that tumor progression in de novo carcinoma is accelerated. These findings should help clarify the concept of de novo carcinoma and contribute to wider recognition of this important clinicopathologic entity.
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PMID:[Are there differences between ex adenoma and de novo colorectal carcinomas?]. 1071 4

Esophageal adenocarcinoma (EAC) is thought to develop through a multistage process in which Barrett's metaplasia progresses through low- and high-grade dysplasia to invasive cancer. Transcriptional silencing of tumor suppressor genes by promoter CpG island hypermethylation has been observed in many types of human cancer. Analysis of CpG island hypermethylation in EAC has thus far been limited to the CDKN2A (p16) gene. In this study, we extend the methylation analysis of EAC to include three other genes, APC, CDH1 (E-cadherin), and ESR1 (ER, estrogen receptor alpha), in addition to CDKN2A. Molecular analysis can provide insight into the complex relationships between tissues with different histologies in Barrett's esophagus and associated adenocarcinoma. Therefore, we have mapped the spatial distribution of methylation patterns in six esophagectomy cases in detail. Hypermethylation of the four CpG islands was analyzed by the MethyLight technique in 107 biopsies derived from these six patients for a total of 428 methylation analyses. Our results show that normal esophageal squamous epithelium is unmethylated at all four CpG islands. CDH1 is unmethylated in most other tissue types as well. Hypermethylation of ESR1 is seen at high frequency in inflammatory reflux esophagitis and at all subsequent stages, whereas APC and CDKN2A hypermethylation is found in Barrett's metaplasia, dysplasia, and EAC. When it occurs, hypermethylation of APC, CDKN2A, and ESR1 is usually found in a large contiguous field, suggesting either a concerted methylation change associated with metaplasia or a clonal expansion of cells with abnormal hypermethylation.
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PMID:Fields of aberrant CpG island hypermethylation in Barrett's esophagus and associated adenocarcinoma. 1101 22

Molecular characterization of eight gastric cancer cell lines established in Japan are summarized according to the genetic and epigenetic alterations and growth factor status. TMK-1 poorly differentiated adenocarcinoma cell line harbors mutant p53 tumor suppressor gene and rearrangement of p15MTS2. MKN-1 adenosquamous carcinoma line with mutant p53 reveals silencing of E-cadherin by promoter CpG hypermethylation. MKN-7 well-differentiated adenocarcinoma cell line has amplification of c-erbB2 oncogene and cyclin E gene. MKN-28 well-differentiated adenocarcinoma cell line reveals mutations in p53 and APC tumor suppressor genes and silencing of CD44. The MKN-45 poorly differentiated adenocarcinoma cell line with wild-type p53 is characterized by homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplification of c-met oncogene and promoter mutation of E-cadherin. MKN-74 derived from moderately differentiated tubular adenocarcinoma has wild-type p53. KATO-III signet ring cell carcinoma line has genomic deletion of p53, amplification of K-sam and c-met oncogene and mutation of E-cadherin. HSC-39 signet ring cell carcinoma cell line harboring p53 missense mutation has homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplifications of c-myc, c-met, K-sam and CD44 gene and mutation in beta-catenin gene.
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PMID:Molecular characteristics of eight gastric cancer cell lines established in Japan. 1110 48

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.
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PMID:Decreased E-cadherin augments beta-catenin nuclear localization: studies in breast cancer cell lines. 1117 84

Participation of E-cadherin in the Wnt signaling pathway was suggested because of the dual role of beta-catenin in cell adhesion and the Wnt signaling cascade. Whereas beta-catenin interacts at the cell membrane with the cell adhesion protein E-cadherin, in the nucleus it activates Wnt target genes through formation of transcriptionally active complexes with members of the Tcf/Lef family of transcription factors. Here, we analyzed by PCR and direct cycle sequencing 26 human breast cancer cell lines for alterations in the E-cadherin gene. Genetic alterations were identified in eight cell lines. Five cell lines had truncating mutations, whereas three cell lines had in-frame deletions in the gene transcript and expressed mutant E-cadherin proteins at the cell membrane. Involvement of E-cadherin in the Wnt pathway was evaluated through determination of the activity of a Tcf reporter gene, which had been transiently transfected into 15 breast cancer cell lines. None of six E-cadherin mutant cell lines and four cell lines that exhibit transcriptional silencing of the E-cadherin gene showed Tcf-mediated transcriptional activation. E-cadherin wild-type cell line DU4475 exhibited constitutive Tcf-beta-catenin signaling activity and was found to express truncated APC proteins. These results indicate that if cellular transformation occurred through mutation of E-cadherin, it is not mediated via constitutive activation of the Wnt signaling pathway.
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PMID:Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. 1119 75

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