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

Much progress has been made in identifying genes mutated during the development of colorectal carcinoma. Mutation of the APC gene in particular appears to be fundamental for colorectal tumour initiation. In contrast, loss of expression of E-cadherin appears to be a late event, which may be important in the development of invasion. Recent clarification of the function of APC, however, has shown that it exists in equilibrium with beta-catenin and E-cadherin. This review discusses the function of these molecules, their interactions, and how APC mutations may alter the equilibrium with beta-catenin and E-cadherin. It is argued that these changes cause aberrant architectural development of tissue, which results in loss of growth control. It is this escape from growth control, rather than acquisition of cell-autonomous growth, which results in the initial development of adenomas. The role of the E-cadherin-catenin unit in colorectal tumour invasion is discussed and the evidence is reviewed for the involvement of APC and E-cadherin in tumours arising from non-intestinal epithelia.
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PMID:The interactions of APC, E-cadherin and beta-catenin in tumour development and progression. 927 21

The E-cadherin-mediated cell adhesion system is now considered to be an "invasion suppressor system" in cancer cells. Dysfunction of the E-cadherin system due to mutations of the genes of E-cadherin and catenins has not been reported in colorectal cancer. Histologically, well-differentiated colorectal cancer cells are found to be scattered at the invasive front in primary lesions and form glands again in metastatic sites. We have reported the association and presence of signal transduction between c-erbB-2/epidermal growth factor receptor (EGF-R) and beta-catenin in human cancer cells. This temporal dysfunction of the E-cadherin system observed in colon cancers may be caused by tyrosine phosphorylation of beta-catenin through activated receptor-type tyrosine kinases. Overexpression of EGF-R and tyrosine phosphorylation of beta-catenin are often observed in "focal dedifferentiated cells" at the invasive front of colorectal cancers. In addition, beta-catenin expression is regulated by the APC tumor suppressor gene product. Thus the E-cadherin-catenin system may play important roles not only in invasion and metastasis but also in the carcinogenesis of colorectal cancer.
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PMID:[Dysfunction of E-cadherin-catenin system in invasion and metastasis of colorectal cancer]. 974 18

The different proteins of the E-cadherin/catenin cell-cell adhesion complex are believed to play a predominant role in carcinogenesis. Aberrant expression of these proteins has been found in many different human carcinomas, indicating abnormal regulation. In general, inactivating mutations of the human E-cadherin gene are rare; they are, however, highly frequent in infiltrating lobular breast carcinomas and in diffuse gastric carcinomas. These mutations mostly occur in combination with loss of heterozygosity (LOH) of the wild-type allele. Mutations were found at very early non-invasive stages, thus associating E-cadherin mutations with loss of growth control and defining E-cadherin as a real tumour suppressor for these particular tumour types. Defects affecting both alleles of the alpha E-catenin gene have been found in different human carcinoma cell lines, resulting in the loss of E-cadherin-mediated cell-cell adhesion. Mutations of the beta-catenin gene in colon tumours and melanomas were found to result in an accumulation of the protein in the cytosol. Upon translocation to the nucleus, this beta-catenin enhances TCF/LEF-dependent transcriptional activity. This suggests that mutated beta-catenin can act as an oncogene in these particular tumour types. The multiple interaction partners of beta-catenin are known to be involved in signal transduction, actin organization, protein phosphorylation or transcriptional regulation. This makes this protein an intriguing alternative target for either activation or inactivation in human cancer types characterized by frequent E-cadherin or APC deficiencies.
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PMID:Dysregulation of the E-cadherin/catenin complex by irreversible mutations in human carcinomas. 982 69

This paper is the first in a series aimed at understanding the role of beta-catenin in epithelial-mesenchymal transformation (EMT) and acquisition of mesenchymal invasive motility. Here, we compare the expression of this and related molecules in the two major tissue phenotypes, epithelial and mesenchymal, the latter including normal avian and mammalian fibroblasts and malignant human uveal melanoma cells. Previously, it was proposed that src initiates EMT by tyrosine phosphorylation of the cadherin/catenin complex resulting in a negative effect on epithelial gene expression. On the contrary, we found that although beta-catenin becomes diffuse in the cytoplasm during embryonic EMT, the cytoplasmic beta-catenin of the embryonic and adult mesenchymal cells we examined is not tyrosine phosphorylated. Pervanadate experiments indicate that cytoplasmic PTPases maintain this dephosphorylation. GSK-3beta is present, but little or no APC occurs in normal and neoplastic mesenchymal cells. The function of the nonphosphorylated cytoplasmic beta-catenin in mesenchyme may be related to invasive motility. Indeed, in order to invade extracellular matrix, transitional (Mel 252) melanoma cells transform from an epithelial to a mesenchymal phenotype with increased cytoplasmic beta-catenin. Moreover, antisense beta-catenin and plakoglobin ODNs inhibit Mel 252 and corneal fibroblast invasion of collagen. All fibroblastic, transitional, and spindle melanoma cells contain nuclear as well as cytoplasmic beta-catenin, but they are not significantly more invasive than normal fibroblasts that contain only cytoplasmic beta-catenin.
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PMID:Tissue-specific expression of beta-catenin in normal mesenchyme and uveal melanomas and its effect on invasiveness. 982 3

The incidence of adenocarcinoma of the distal esophagus is rapidly increasing in the Western world. The histopathological sequence of (Barrett's) metaplasia, which develops as a consequence of chronic reflux, to dysplasia and then to carcinoma is well established for these tumors. In Barrett's esophagus a variety of molecular changes have been characterized and correlated with tumor initiation and progression. Among the early changes in premalignant stages of metaplasia are alterations of the transcripts of FHIT, a presumptive tumor suppressor gene which spans the common fragile site FRA3B. Mutations of p53 seem to accumulate mainly in the transition from low to high grade dysplasia. Inactivation of other tumor suppressor genes by mutation (APC, p16) or hypermethylation (p16) as well as amplification of oncogenes such as cerbB2 are relatively late events in the development of adenocarcinoma. Among the phenotypic changes in Barrett's esophagus are an expansion of the Ki67 proliferation compartment which correlates with the degree of dysplasia. Moreover, accumulation of rab11 molecules which are involved in membrane trafficking has been reported to be specific for the loss of polarity seen in low grade dysplasia. Reduced expression of the cadherin/catenin complex as well as increased expression of various proteases develop chiefly in invasive carcinomas. Despite the progress that has been made in the identification of molecular markers in Barrett's carcinoma, to date the histopathological diagnosis of high grade dysplasia in endoscopic biopsies remains the best predictor of invasive cancer. Immunohistochemistry applying a panel of antibodies including p53, Mib-1 or rab11 can be helpful to diagnose regenerative metaplastic epithelium or low and high grade dysplasia.
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PMID:The molecular pathology of Barrett's esophagus. 1021 17

beta-catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also functions in growth signalling events, independently of the cadherin-catenin complex, and these signalling pathways are disturbed in colorectal cancer. Mutations in either the APC or beta-catenin genes in colorectal cancer cells result in up-regulation of protein expression and subsequent cytoplasmic and nuclear distribution of beta-catenin. In this study, we examined beta-catenin expression in 47 primary colorectal tumors and the corresponding liver metastases. Immunohistochemical studies demonstrated loss of membranous beta-catenin expression in 26% of primary tumors and 60% of liver metastases and a concomitant increase in cytoplasmic and nuclear staining. Widespread nuclear expression of beta-catenin was found in 64% of primary tumors and 21% of liver metastases. No associations were found between any form of beta-catenin expression and either tumor stage or tumor grade. Cellular distribution of beta-catenin was also examined by detergent extraction and Western blot analysis in 16 primary tumors and 23 liver metastases. This analysis showed that most tumors demonstrated reduced beta-catenin in the cytoskeletal fraction and increased beta-catenin in the cytosolic fraction. Furthermore, 3 liver metastases were found to contain a truncated beta-catenin protein of approximately M(r) 80,000. Immunoprecipitation studies showed that the truncated beta-catenin proteins only bound weakly to E-cadherin and beta-catenin compared with non-truncated beta-catenin. These results demonstrate gross alterations in the cellular distribution of beta-catenin in primary colorectal cancers with metastatic potential, as well as in the metastatic tumors. These changes may be the consequence of APC or beta-catenin gene mutations, or possibly result from a post-translational modification of the E-cadherin-catenin complex.
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PMID:beta-catenin expression in primary and metastatic colorectal carcinoma. 1040 62

Cadherins are transmembrane cell-cell adhesion molecules which are connected to the cytoskeleton by association with the cytoplasmic proteins, alpha-, beta-, and, gamma-catenin (plakoglobin). Beta-catenin has an additional role in the wnt signal transduction pathway in which it transmitts signals to the cell nucleus in complexes with transcription factors of the LEF-1/TCF family. The cell adhesion function of the epithelial E-cadherin is frequently disturbed in carcinomas either by downregulation or by mutation of the E-cadherin/catenin genes. The signaling function of beta-catenin is activated in tumors by mutations of beta-catenin or of the tumor suppressor gene product APC. In this review I will give an introduction to the structure and function of the cadherin/catenin complex and summarize findings which support a decisive role of these components in the development of cancer.
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PMID:Cadherins and catenins: role in signal transduction and tumor progression. 1050 43

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

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

In recent years developmental biology has contributed a great deal to cancer research. This is in part because both fields address the question of how genes control the three-dimensional organisation of tissues, and how mutation of genes alters this. But also in recent years, the discovery that signalling pathways are conserved from worms to man, combined with the power of developmental biology's model organisms, principally Drosophila and C. elegans, to reveal signalling pathways that control tissue growth and organisation, has had a huge impact. Examples of this are the subject of the reviews in this issue, including the EGF-receptor, Wnt/APC/catenin, TGF-beta/Smad and hedgehog/patched/smoothened pathways, all of which were discovered and/or pieced together in model organisms, and all of which are disrupted by mutation in human cancer. Other topics considered are the control and execution of apoptosis; the search for tumour-suppressor-like genes in Drosophila; and genes of the Polycomb and Trithorax Groups that regulate the commitment of cells to patterns of differentiation, and that are among the targets for chromosome translocations. These stories illustrate how developmental biology has shown that there are many more signalling pathways relevant to neoplasia than the receptor tyrosine kinase pathways that first dominated the field; and that the signalling is more than just mitogenic or anti-mitogenic, and should be viewed as providing cells with information about their position and neighbours, that determines their role, differentiation and behaviour.
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PMID:The impact of developmental biology on cancer research: an overview. 1072 82


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