Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Simultaneous deregulation of both Wnt and ErbB growth factors has previously been shown to result in the cooperative induction of mammary gland tumors. Using the murine mammary tumor virus (MMTV)-Wnt-1 transgenic model of mammary carcinoma, we have identified an unvarying association between beta-catenin and epidermal growth factor receptor/c-Neu (ErbB1/ErbB2) heterodimers in mammary gland tumors, indicating a requirement for ErbB signaling in Wnt-mediated tumorigenesis. Expansion of these observations to a second transgenic model, MMTV-c-Neu, demonstrated similar tumor-specific interactions, including an ErbB1 ligand-inducible phosphorylation of both beta-catenin and c-Neu. Direct relevance of these findings to human breast cancer was established upon examination of a set of human infiltrating ductal breast adenocarcinoma and lymph node metastasis tissues taken at surgery. These data revealed increased levels of beta-catenin in tumors and metastases versus normal breast as well as an association between beta-catenin and c-Neu that measurably occurs only in neoplasia, most strongly in metastatic lesions. These studies have identified a seemingly indispensable interaction between beta-catenin and epidermal growth factor receptor/c-Neu heterodimers in Wnt-1-mediated breast tumorigenesis that may indicate a fundamental signaling event in human metastatic progression.
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PMID:ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas. 1195 Aug 45

beta-Catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also plays a role in the Wnt signaling pathway by activating T-cell factor- and lymphoid enhancer factor-regulated gene transcription. The level of beta-catenin in cells is tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation sites of the beta-catenin gene (CTNNB1) result in nuclear and/or cytoplasmic accumulation of beta-catenin and constitutive transactivation of T-cell factor and lymphoid enhancer factor target genes, a mechanism occurring in many cancers. Melanoma cell lines may harbor beta-catenin mutations; in vivo, however, cellular accumulation of beta-catenin is rarely caused by CTNNB1 mutations. In our study, 43 primary cutaneous melanoma and 30 metastases were screened for CTNNB1 exon 3 mutations by using a denaturing gradient gel electrophoresis technique and sequencing. beta-Catenin mutations were found in 2 primary melanomas and 1 metastatic melanoma and were not correlated with nuclear accumulation of beta-catenin in these cases. Cellular expression of beta-catenin was evaluated by immunohistochemistry and by reverse polymerase chain reaction (RT-PCR) in 80 and 70 cases, respectively. Immunohistochemistry revealed a significant loss of membranous beta-catenin staining between the primary and metastatic melanomas as well as between radial and vertical growth phase. RT-PCR showed a significant inverse correlation between the amount of RNA and the proportion of cells with membranous expression of beta-catenin (P =.0015); no correlation existed between the amount of RNA and the number of cells with nuclear or cytoplasmic expression of beta-catenin. In conclusion, nuclear expression of beta-catenin is seen in cutaneous melanoma but, in contrast to the case of many other cancers, does not correlate with tumor stage or mutation status. A combination of immunohistochemistry and RT-PCR showed that down-regulation of membranous beta-catenin was associated with an increased amount of beta-catenin RNA in primary or metastatic melanoma. Our results suggest that posttranslational events, rather than CTNNB1 mutations, are responsible for the altered distribution of beta-catenin in cutaneous melanoma.
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PMID:Loss of membranous expression of beta-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations. 1195 Sep 21

E-cadherin and the catenins are responsible for inter-cellular adhesion in epithelial tissues. E-cadherin and/or catenin expression is often altered in malignancies, leading to increased invasiveness and metastatic activity of tumour cells. Intact adhesion molecules reduce the risk on distant metastases. This is confirmed by studies mostly performed on surgical series, correlating e-cadherin expression in tumours with prognosis and treatment outcome. It has become more apparent that anti-cancer treatment by itself can also affect the expression of adhesion molecules. We therefore suggest that the prognostic value of e-cadherin expression may depend on the treatment modality and the sequence of therapies administered for malignant tumours. We used paraffin embedded specimens from patients with rectal tumours and patients with laryngeal tumours treated by short course radiotherapy before definitive surgery. Expression of p53, e-cadherin, and beta-catenin was determined in pre-radiotherapy biopsies and in the surgical specimens. Material was available from 37 patients. We found no correlation between the expression of p53, e-cadherin or beta-catenin and pre-treatment parameters. Mutated p53 in pre-radiation biopsy correlated with increased occurrence of distant metastases and there was an unexpected trend for abnormal e-cadherin expression to correlate with reduced metastases. The prognostic value of p53 no longer existed after examination of the surgical specimens (post-radiotherapy). There was a trend for e-cadherin to reverse from abnormal to normal expression in laryngeal squamous cell carcinomas after radiotherapy, in 5/7 cases it was accompanied with p53 conversion from positive to negative expression. Based on this study it is suggested that the predictive value of the e-cadherin expression for the occurrence of distant metastases in tumours treated by radiotherapy before surgery may be different from that found in tumours treated by surgery only. This may be related to the influence of radiotherapy on e-cadherin expression, especially in squamous cell carcinomas. Alteration in p53 expression was of predictive value only in pre-treatment biopsies and the beta-catenin status did not correlate with treatment outcome in this series.
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PMID:The influence of pre-operative radiotherapy on the expression of p53 and adhesion molecules: correlation with treatment results in patients with squamous cell carcinoma or adenocarcinoma. 1195 39

Epithelial-mesenchymal transformation (EMT) is an important process in development that is characterized by loss of E-cadherin, beta-catenin relocalization, and acquisition of elongated cell shape and ability to invade ECM. beta-catenin has been shown to activate LEF-1 transcription during EMT induced in vitro by c-Fos. Here, we ask whether or not LEF-1 directly introduced into epithelial cells in an adenovirus construct can induce EMT. In normal epithelial cell lines, such as HCE and MDCK cells, that contain functional APC, nuclear beta-catenin induced by exogenous LEF-1 is rapidly exported and EMT is not induced. Leptomycin-B blocks beta-catenin nuclear export, but no EMT occurs due to toxicity. Addition of Wnt-1 to normal epithelial cell lines stabilizes cytoplasmic beta-catenin that LEF-1 then transports to nuclei, causing a small amount of EMT. Our experiments demonstrated, however, that overexpressed LEF-1 upregulates nuclear beta-catenin and promotes dramatic EMT in DLD-1 epithelial tumors that retain nuclear beta-catenin. This EMT is reversible if the LEF-1 virus is removed. Thus, our results demonstrate that LEF-1 can induce EMT directly when its transcription activity is activated by stable nuclear beta-catenin. Normal adult epithelial cells appear to use APC to keep beta-catenin out of the nucleus, thereby avoiding pathologies such as metastases due to LEF/beta-catenin-induced EMT.
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PMID:Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. 1209 32

Aberrant activation of the Wnt signaling pathway has been reported in different human tumor types, including malignant melanomas. We investigated 37 malignant melanomas (15 primary tumors and 22 metastases) for alterations of 4 genes encoding members of this pathway, i.e., CTNNB1 (beta-catenin gene, 3p22.1), APC (adenomatous polyposis coli gene, 5q22.2), BTRC (beta-transducin repeat-containing protein gene, 10q24.3) and ICAT (inhibitor of beta-catenin and Tcf-4, 1p36.2). Mutational analysis of CTNNB1 identified somatic mutations in 1 primary melanoma and 1 melanoma metastasis from 2 different patients (5%). Both mutations affected the N-terminal degradation box of beta-catenin, which is important for the regulation of beta-catenin homeostasis. Another primary melanoma carried a somatic APC missense mutation within the known mutation cluster region in exon 15. Fourteen tumors (40%) showed LOH at microsatellite markers on 1p36. None of the tumors had lost both copies of the ICAT gene, but 1 melanoma metastasis carried a somatic point mutation altering the translation start codon of ICAT. Real-time RT-PCR showed markedly reduced ICAT transcript levels (<or=20% relative to normal skin and benign melanocytic nevi) in 28/36 malignant melanomas (78%), including 13/14 tumors with LOH on 1p36. Allelic loss on 10q was detected in 15 tumors (44%). We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series. Taken together, our results indicate that the Wnt pathway may be altered in malignant melanomas by different mechanisms, including rare somatic mutations in CTNNB1, APC or ICAT, as well as low or absent expression of ICAT transcripts.
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PMID:Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. 1212 4

E-cadherin and catenins play a major role in neoplastic cell behavior as a suppressor of invasion and/or metastasis. The aim of this study was to determine E-cadherin, alpha-catenin and beta-catenin expressions in papillary thyroid carcinoma (PTC) and to correlate the results of expression to initial clinicopathological parameters and clinical outcome. Forty-one cases (mean age 37.3 +/- 11.2 yr) with PTC were studied. Patients were followed-up with a mean period of 47.6 +/- 27.0 months. A retrospective immunohistochemical analysis of E-cadherin, alpha-catenin and beta-catenin was performed on paraffin-embedded tissue sections. Tissues from ten patients with benign goiter were used as controls. E-cadherin, alpha- and beta-catenin immunoreactivities were found in 80% (33/41), 76% (31/41) and 97% (40/41) of patients respectively. No correlation was found between E-cadherin, alpha- and beta-catenin immunoreactivities and sex, local invasion or lymphatic spread at the time of initial examination. Distant metastases and/or local recurrences developed in 6 patients during follow-up. Recurrences/metastases developed both E-cadherin, alpha- and beta-catenin positive and negative primary tumors. Disease-free survival curves according to Kaplan-Meier analysis and log-rank test did not show any significant differences between E-cadherin, alpha- and beta-catenin positive and negative patients. According to our findings, E-cadherin, alpha- and beta-catenin expressions may not add any valuable information to the follow-up in a subgroup of PTC patients with a relatively benign course.
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PMID:Immunohistochemical detection of E-cadherin, alpha- and beta-catenins in papillary thyroid carcinoma. 1215 Mar 30

Lymph node metastasis is commonly found in esophageal squamous cell carcinoma (SCC). In this study, we examined the molecular and genetic characteristics of a human esophageal SCC cell line, T.Tn. T.Tn cells formed tumors at s.c. tissue in nude mice when inoculated with Matrigel, but did not metastasize to any organs. T.Tn cells expressed low level of proMMP2 and a trace level of proMMP9. However, T.Tn cells expressed high level of TIMP1 and TIMP2, and beta-catenin and E-cadherin. We found a point mutation of p53 gene at codon 213 (CAT-->CGT) in T.Tn cells. The mutated-p53 protein did not show transcriptional activity on p21(waf1), MDM2 and Bax promoters. Thus, T.Tn cells are low tumorigenic and weakly invasive but not metastasizing in nude mice, and T.Tn cells are suitable parental cells for establishing a model system to study invasion and metastasis of esophageal SCC.
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PMID:Molecular and genetic characterization of a non-metastatic human esophageal cancer cell line, T.Tn expressing non-functional mutated p53. 1216 98

The E-cadherin/catenin complex plays a major role in epithelial cell-cell adhesion. Both beta-catenin and gamma-catenin bind directly to the cytoplasmic domain of E-cadherin whereas alpha-catenin links the bound beta-catenin or gamma-catenin to the actin microfilament network of the cellular cytoskeleton. Significant changes in the expression and/or structure of members of the complex can occur in neoplasia. Several studies have reported on the nuclear localization of beta- and gamma-catenin and on their role in influencing the transcriptional activity of several proto-oncogenes. The cellular localization of alpha-catenin has not been studied in detail. The aim of this study was to investigate the cellular localization of alpha-catenin in colorectal carcinoma both in vitro and in vivo and to assess whether it might be relevant to tumor behavior. The expression of alpha-catenin was examined in a panel of colorectal carcinoma cell lines (SW480, SW620, HCT116, HT29, and Caco-2) using a combination of immunohistochemistry, confocal fluorescence microscopy, and Western blotting. The expression of alpha-catenin was also studied by immunohistochemistry in 15 sporadic colorectal adenomas, 30 sporadic colorectal adenocarcinomas, and their 13 lymph node metastases. From familial adenomatous polyposis patients, 20 adenomas and 5 adenocarcinomas were studied. Nuclear localization of alpha-catenin was detected in the colorectal carcinoma cell lines when the cells were dispersed rather than confluent. alpha-catenin was not detected in the nuclei in any of the sporadic or familial adenomas. However, it was detected in one sporadic and one familial adenocarcinoma but not in any of the lymph node deposits. alpha-catenin can localize to the nuclei of colorectal tumor cells, and this may be related to lack of perception of connection to adjacent cells.
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PMID:Variable nuclear localization of alpha-catenin in colorectal carcinoma. 1221 77

The aim of this study was to define whether or not the impaired expression of CD44, E-cadherin (E-cad), and beta-catenin (beta-cat) correlates with the clinical evolution and prognosis of oral cancer. Ninety-three primary oral squamous cell carcinomas (OSCCs) with tumour-adjacent normal and/or dysplastic mucosa, 30 associated metastases, and 12 recurrences were immunostained for CD44s, -v3, -v4, -v5, -v6, -v7, -v9, E-cad, and beta-cat. In non-neoplastic epithelium, all molecules investigated were constitutively expressed in the basal layers. In the majority of dysplasias, immunoreactivity for all adhesion molecules was increased, but there was restricted loss for CD44s, E-cad, and beta-cat in a few cases. In carcinomas, a striking accumulation of CD44s, v3, v4, v9 and a loss of E-cad/beta-cat were observed at the invasive tumour front. In metastases and recurrences, besides a loss of CD44s, v4, v7, and E-cad, a significant increase of v9 was recorded, whereas CD44v5 and v6 remained unchanged. Clinically, reduced expression of CD44v3, E-cad, and changes of CD44v9 phenotype within the primary tumours correlated significantly with poor prognosis; decreased beta-cat expression was a predictive marker for nodal metastases. These findings indicate that there is some perturbed expression of adhesion molecules during the stepwise course of oral carcinogenesis and tumour progression. Distinct phenotypic alterations project poor prognosis, while others predict metastasis. Some of these restricted molecular changes may serve as potential targets for future antibody-based tumour therapy.
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PMID:Gains and losses of adhesion molecules (CD44, E-cadherin, and beta-catenin) during oral carcinogenesis and tumour progression. 1237 67

Beta-catenin plays a dual role as a major constituent of cadherin-based adherens junctions and also as a transcriptional coactivator. In normal ephitelial cells, at adherens junction level, beta-catenin links cadherins to the actin cytoskeleton. The structure of adherens junctions is dynamically regulated by tyrosine phosphorylation. In particular, cell-cell adhesion can be negatively regulated through the tyrosine phosphorylation of beta-catenin. Furthermore, the loss of beta-catenin-cadherin association has been correlated with the transition from a benign tumor to an invasive, metastatic cancer. Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) is a ubiquitous PTP implicated in the regulation of mitosis and cytoskeleton rearrangement. Here we demonstrate that the amount of free cytoplasmic beta-catenin is decreased in NIH3T3, which overexpresses active LMW-PTP, and this results in a stronger association between cadherin complexes and the actin-based cytoskeleton with respect to control cells. Confocal microscopy analysis shows that beta-catenin colocalizes with LMW-PTP at the plasma membrane. Furthermore, we provide evidence that beta-catenin is able to associate with LMW-PTP both in vitro and in vivo. Moreover, overexpression of active LMW-PTP strongly potentiates cadherin-mediated cell-cell adhesion, whereas a dominant-negative form of LMW-PTP induces the opposite phenotype, both in NIH3T3 and in MCF-7 carcinoma cells. On the basis of these results, we propose that the stability of cell-cell contacts at the adherens junction level is positively influenced by LMW-PTP expression, mainly because of the beta-catenin and LMW-PTP interaction at the plasma membrane level with consequent dephosphorylation.
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PMID:Beta-catenin interacts with low-molecular-weight protein tyrosine phosphatase leading to cadherin-mediated cell-cell adhesion increase. 1243 42


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