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)

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

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.
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PMID:beta-Catenin regulates vascular endothelial growth factor expression in colon cancer. 1281 Jun 42

Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor of unknown origin and pathogenesis. We clinicopathologically analyzed 16 cases of ASPS and screened for the genetic alterations of various tumor-suppressor genes and oncogenes, including p53, adenomatous polyposis coli (APC), E-cadherin, and beta-catenin, in 11 cases of ASPS. We also examined the expression of hMSH2/hMLH1 of DNA mismatch repair genes by immunohistochemistry, and promoter hypermethylation of these DNA mismatch repair genes by methylation-specific polymerase chain reaction (MS-PCR) to elucidate any possible association between mutation status of these genes and inactivation of the hMSH2/hMLH1 genes. Furthermore, microsatellite instability (MSI) analysis and loss of heterozygosity (LOH) on chromosome 5q analysis were used for some cases of ASPS where DNA derived from normal tissue was available. The 5-year overall survival rate for all of the patients in this study was 68.6%. The 5-year overall survival rates for patients presenting with localized ASPS and for patients with distant metastases were 83.3% and 47.6%, respectively. The high nuclear grade of tumor cells was a significantly adverse prognostic factor (P = 0.0085). Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 4 point mutations of the p53 gene in 3 of 11 cases (27.3%), composed of 3 missense mutations and 1 silent mutation. In addition, 1 case with the E-cadherin missense mutation and 1 case with the APC missense mutations were observed, respectively. None of the cases harbored mutation of exon 3 of the beta-catenin gene. Loss of expression of the hMSH2 and hMLH1 genes was observed in 2 (18.2%) and 3 (27.3%) of 11 cases, respectively. All 3 cases with loss of hMLH1 gene expression harbored mutations of the p53 gene. There was a statistically significant correlation between the genetic alteration positive in these tumor-suppressor genes and loss of hMLH1 gene expression (P = 0.024). Methylation-specific PCR did not reveal hypermethylation of the hMSH2/hMLH1 promoter region in any of the cases examined. Three of 8 (37.5%) ASPS cases showed low MSI, and 2 of these 3 cases showed immunohistochemical lack of expression for either hMSH2 or hMLH1. LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.
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PMID:Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma. 1456 78

The MUC1 tumor antigen is overexpressed on most breast tumors and metastases. It interacts with signaling proteins such as the ErbB kinases and beta-catenin, and is involved in mammary gland oncogenesis and tumor progression. Herein, we report a novel interaction between MUC1 and adenomatous polyposis coli (APC), a tumor suppressor involved in downregulating beta-catenin signaling. Initially identified in colorectal cancer, APC is also downregulated in breast tumors and presumably involved in mammary carcinogenesis. MUC1 and APC co-immunoprecipitate from the ZR-75-1 human breast carcinoma cell line and co-localize in mouse mammary glands and tumors. These studies also indicate that the association of MUC1 and APC may be increased by epidermal growth factor stimulation. Intriguingly, the co-immunoprecipitation of MUC1 and APC increases in human breast tumors and metastases as compared to adjacent normal tissues, indicating that this association may play a role in the formation and progression of breast tumors.
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PMID:MUC1 can interact with adenomatous polyposis coli in breast cancer. 1502 Feb 26

Endometrial carcinoma, generally, has a good prognosis. However, in some patients, the tumor appears to behave very aggressively, a course that cannot be explained with histopathological characteristics. More insight into the molecular background can be valuable to clarify these differences in tumor behavior. The three components associated with the Wnt pathway--i.e., adenomatous polyposis coli (APC), beta-catenin, and E-cadherin--were evaluated in a case-control study of 28 patients with stage-I endometrial carcinomas to determine their involvement in the development of recurrent disease. Mutation analysis of the mutation cluster region of the APC gene, determination of gene promoter methylation status of the APC-1A and E-cadherin genes, and immunohistochemical analysis of APC, E-cadherin, and beta-catenin were performed using paraffin-embedded tumor tissue. Twenty-one APC gene mutations were detected in 12 of 28 (43%) patients. Only three mutations would result in a stopcodon in the APC gene. APC gene promoter methylation was assessed in 12 of 28 (43%) patients. APC immunostaining was absent in two of 24 (8.3%) patients. The occurrence of APC mutations, APC gene promoter methylation, and APC immunostaining were not predictive for recurrence. No E-cadherin expression was observed in four of 24 patients (17%). E-cadherin gene promoter methylation could not be detected in any of the patients. The absence of E-cadherin expression was predictive for distant metastases, but not for local recurrence. Nuclear localization of beta-catenin was present in nine of 24 (38%) patients and was not predictive for recurrent disease. Involvement of epigenetic and genetic aberrations in APC and beta-catenin genes seems to be of minor importance for the development of local recurrences and distant metastases. Although the number of patients is limited, E-cadherin expression appears to be predictive for the development of distant metastases in endometrial carcinoma.
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PMID:APC, beta-catenin, and E-cadherin and the development of recurrent endometrial carcinoma. 1536 Dec 8

APC (adenomatous polyposis coli) promoter methylation has been linked to the early development of colorectal cancers. However, the role of APC methylation and its effect on protein expression in colon cancer metastasis is largely unknown. In this study, we investigated APC promoter methylation by Methylight analysis and analysed the APC protein levels by immunohistochemistry and western blot analysis in 24 liver metastasis and 39 primary colorectal cancers. Promoter methylation of the APC gene was found to be a frequent event in liver metastasis (10/24) and significantly more frequent compared with primary colorectal cancer (7/39, P = 0.047). APC methylation was not found in 14 matched normal colon tissues. APC protein was detected in the cytoplasm of primary and metastatic cancer cells and non-tumorous colon epithelium. By western blot analysis, APC protein levels were found to be decreased in primary tumour tissues compared with the normal colon mucosa. In contrast, APC protein levels were not decreased in the cancer cells that had metastasized to the liver. APC protein levels were independent of the presence of APC promoter methylation or gene mutations. In summary, APC promoter methylation is a frequent epigenetic alteration in colorectal cancer metastasis. However, we observed no significant association between APC promoter methylation or gene mutation and APC protein expression in colorectal metastasis. Therefore, metastatic cancer cells seem to harbour a heterogenous genetic and epigenetic background, in which cancer cells may exhibit APC promoter methylation that is independent of APC expression.
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PMID:Molecular analysis of APC promoter methylation and protein expression in colorectal cancer metastasis. 1537 9

Deep fibromatoses (desmoid tumors) are clonal myofibroblastic proliferations that are prone to aggressive local recurrences but that do not metastasize. They must be distinguished from a host of fibroblastic and myofibroblastic lesions as well as from smooth muscle neoplasms. Virtually all deep fibromatoses have somatic beta-catenin or adenomatous polyposis coli (APC) gene mutations leading to intranuclear accumulation of beta-catenin. Since low-grade sarcomas in general lack beta-catenin and since reactive proliferations would not be expected to have it, we predicted that nuclear beta-catenin expression would be detected in deep fibromatoses but absent in other entities in the differential diagnosis. We evaluated the role of beta-catenin to help differentiate distinguish deep fibromatoses from congeners. Formalin-fixed, paraffin-embedded sections from 21 lesions from 20 patients with deep fibromatoses were stained with monoclonal beta-catenin antibody (Transduction Laboratories) and compared with low-grade fibromyxoid sarcoma (n=12), leiomyosarcoma (n=10), various other fibrosarcoma variants (n=13, including 3 myofibrosarcomas, 3 sclerosing epithelioid fibrosarcomas, 5 low-grade fibrosarcomas, 1 classic fibrosarcoma arising in dermatofibrosarcoma protuberans, 1 inflammatory myxohyaline tumor/myxoinflammatory fibroblastic sarcoma), myofibroma/myofibromatosis (n=12), nodular fasciitis (n=11), and scars (n=9). Nuclear and cytoplasmic staining was assessed. All 21 examples of deep fibromatosis displayed nuclear beta-catenin (focal nuclear staining in one case to 90% staining). All other lesions tested (n=67) lacked nuclear labeling for beta-catenin, showing only cytoplasmic accumulation. beta-Catenin immunohistochemistry separates deep fibromatosis from entities in the differential diagnosis, a finding that can be exploited for diagnosis. Most fibromatoses have diffuse nuclear staining although occasional examples only focally label.
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PMID:Nuclear beta-catenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. 1583 90

The histological features that accompany the development and progression of solid tumors are known to be controlled by a distinct cascade of molecular events. One such event is the inactivation of tumor suppressor genes, such as the adenomatous polyposis coli (APC) gene. Disruption of the cadherin-catenin cell adhesion complex also plays a role in the initial steps of cancer invasion and metastasis whereas alterations in cell structural molecules, such as tubulin, may contribute to the cancer phenotype. The understanding of the status of these molecules in ESSC may provide novel markers that could impact on management of the disease. The present study examined alterations in the microsatellite sequence of the APC gene via fluorescent-based polymerase chain reaction in 100 cases of primary esophageal squamous cell carcinoma. In addition, the expression of E-cadherin, alpha- and beta-catenin, and alpha- and beta-tubulin was analyzed using immunohistochemistry. These data were then statistically compared with each other as well as the relevant clinicopathologic data. Although the APC markers (D5S210, D5S346, D5S299, and D5S82) tested did show an overall high frequency of allelic imbalance/loss of heterozygosity (62.48%) and microsatellite instability (41.27%), they did not show prognostic significance in the study cohort and were not correlated with the immunohistochemical data. The tubulin proteins showed no significant change in expression in the tumor tissue The decreased immunoreactivity of E-cadherin was statistically correlated with the presence of lymph node metastases (P = .0180). Although alpha- and beta-catenin as well as E-cadherin showed no direct prognostic value, E-cadherin may warrant further investigation as an indirect prognostic indicator by allowing more accurate prediction of lymph node metastases.
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PMID:Microsatellite analysis of the APC gene and immunoexpression of E-cadherin, catenin, and tubulin in esophageal squamous cell carcinoma. 1642 11

Malignant progression of colorectal carcinomas is characterized by an epithelial-mesenchymal transition (EMT)-like de-differentiation of the invading tumor cells. However a re-differentiation towards an epithelial phenotype, resembling a mesenchymal-epithelial transition (MET), is detectable in metastases. This indicates that malignant progression is based on dynamic processes, which can not be explained solely by irreversible genetic alterations, but must be additionally regulated by the tumor environment. The main oncoprotein in colorectal cancer is the Wnt-pathway effector beta-catenin, which in most cases is overexpressed due to mutations in the adenomatous polyposis coli (APC) tumor suppressor. EMT of tumor cells is associated with a nuclear accumulation of the transcriptional activator beta-catenin, which is reversed in metastases. Nuclear beta-catenin is involved in two fundamental processes in embryonic development: EMT and stem cell formation. Accumulating data demonstrate that aberrant nuclear expression of beta-catenin can also confer these two abilities to tumor cells, indicating the crucial role of aberrant Wnt-signaling for malignant tumor progression.
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PMID:Wnt/FZD signaling and colorectal cancer morphogenesis. 1712 10

Sporadic colon cancer is a major cause of death throughout the world. Multistage development of the disease has been associated with remarkable genetic events, mainly at the level of oncogenes and oncosuppressor genes, most notably APC (adenomatous polyposis coli), ras and p53. Despite all of these efforts, the development of a sensitive and convenient diagnostic system for detecting colorectal cancers at the early stage is still in progress. In recent years, cDNA and oligonucleotide microarray technologies have made the analysis of gene expression profiles of colorectal tumours at the genomic level possible and have identified signatures of gene expression associated with pre-cancerous phenotypes, cancers of the early stage and/or metastatic cancer. The contribution of this powerful technology in identification of novel important genes for prognosis, diagnosis and therapy of sporadic colorectal will be discussed.
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PMID:Microarray analysis to reveal genes involved in colon carcinogenesis. 1747 35


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