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)

This study examined the relationship between the expression of E-cadherin or beta-catenin in murine adenocarcinomas and their hematogenous metastatic propensity, assessed by both spontaneous and artificial lung metastasis. Seven different carcinomas, syngeneic to C3Hf/Kam mice were used: 4 mammary carcinomas (MCa-4, MCa-29, MCa-35, and MCa-K), ovarian carcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG. These tumors vary widely in their ability to spontaneously metastasize to the lung (from 0 to 100% metastatic incidence), and their cells greatly differ in their ability to form artificial lung nodules when injected i.v. Primary tumors in the leg were assessed for E-cadherin and beta-catenin expression by western blotting. The expression of both proteins showed wide variation among the tumors; however, the expression of E-cadherin correlated well with that of beta-catenin. There was significant inverse correlation between the expression of E-cadherin, as well as beta-catenin, and the incidence of both spontaneous and artificial lung metastases from these tumors. Spontaneous metastases of highly metastatic HCa-I and moderately metastatic MCa-35 were significantly lower in E-cadherin and beta-catenin expression than their corresponding primary tumors were. Thus, the propensity of murine carcinomas for hematogenous spread is highly related to E-cadherin and beta-catenin levels in primary tumors. The inverse correlation between the expression of these molecules and spontaneous and artificial metastases implies that tumor cells with low E-cadherin and beta-catenin content have increased ability to enter the vascular circulation at the primary tumor site and to colonize distant tissues.
Clin Exp Metastasis 1999 Mar
PMID:Low E-cadherin and beta-catenin expression correlates with increased spontaneous and artificial lung metastases of murine carcinomas. 1041 Nov 10

Our previous study in extramammary Paget's disease showed neither p53 mutations nor allelic loss at selected loci implicated in other cancers, suggesting a pathogenesis of this skin cancer different from other common epithelial malignancies. To examine further the genetic defects in extramammary Paget's disease, we carried out molecular genetic analyses in 31 tumor samples obtained from 27 cases of extramammary Paget's disease without underlying malignancies. Immunohistochemistry using CB-11 monoclonal antibody revealed either membrane or cytoplasmic erbB-2 oncoprotein overexpression in none of the 13 primary in situ tumors, but in one recurrent in situ tumor, 10 of 13 invasive primary tumors and two of four lymph node metastases. Sensitive dual color fluorescence in situ hybridization analysis using probes for erbB-2 gene locus and chromosome 17 pericentromere, however, revealed different erbB-2 gene status in the erbB-2 overexpressing tumors. One recurrent in situ tumor and one lymph node metastasis showed definite gene amplification characterized by multiple scattered signals or a few large clustered erbB-2 signals, whereas four tumors with predominantly cytoplasmic erbB-2 overexpression were thought to have low-grade gene amplification. The remaining six tumors overexpressing erbB-2 showed no increase of erbB-2 copy numbers. No evidence of abnormal activation of the beta-catenin gene, a critical mediator of Wnt signaling pathway, in any tumor by immunohistochemical staining and by direct sequencing and reverse transcription-polymerase chain reaction analysis was found. Frequent overexpression of erbB-2 by either gene amplification or possible transcriptional activation in invasive primary tumors and metastases suggests an important part for this oncogene in the progression of extramammary Paget's disease.
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PMID:erbB-2 overexpression but no activation of beta-Catenin gene in extramammary Paget's disease. 1046 13

E-cadherin mediated intercellular adhesion is regulated by a family of cytoplasmic proteins that include alpha-, beta- and gamma-catenin and p120cas. Changes in expression of E-cadherin are believed to be an early event in melanoma development. Recent studies have also drawn attention to the over-expression of beta-catenin and its possible indirect role as an oncogene in melanoma. In view of these studies, we have examined the expression of cytoplasmic proteins immunohistochemically in 13 melanocytic nevi, 34 primary cutaneous melanomas and 20 metastatic melanomas. alpha-, gamma-catenin and p120cas were heterogeneously expressed in melanocytic nevi and melanomas and were frequently absent, whereas beta-catenin expression was observed in all lesions. The pattern of expression of alpha-, beta- and gamma-catenin and p120cas was characterised by cytoplasmic and membranous immunoreactivity of varying intensity. No significant difference was found in expression of these proteins between melanocytic nevi and primary melanoma. In contrast, there was an inverse correlation between alpha-catenin expression and tumor thickness and alpha-catenin was more frequently expressed in radial compared to vertical growth phase in primary melanoma. Loss of alpha-catenin expression was observed in ten of 20 metastases compared to six of 34 primaries and the expression was more marked in primaries than in metastases. These results indicated that alterations in alpha-, beta- and gamma-catenin and p120cas expression were common in melanocytic nevi and melanomas, and that loss of alpha-catenin expression was associated with melanoma invasiveness and metastasis.
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PMID:Expression of catenins and p120cas in melanocytic nevi and cutaneous melanoma: deficient alpha-catenin expression is associated with melanoma progression. 1050 70

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.
Cancer Metastasis Rev 1999
PMID:Cadherins and catenins: role in signal transduction and tumor progression. 1050 43

Cell adhesion molecules belonging to the integrin, cadherin and immunoglobulin superfamilies have been implicated in tumor progression in cutaneous melanoma. Expression of the alpha v beta 3 integrin first appears with the change from radial to vertical growth, a step which is associated with the development of metastatic potential. VLA-4 expression is characteristic of advanced primary tumors and may mediate interaction of the tumor cells with VCAM-1 on vascular endothelium. Expression of these integrins is a marker of poor prognosis in patients and can confer invasive (alpha v beta 3) and metastatic (VLA-4) properties to human melanoma cells injected into nude mice. Expression of the immunoglobulin superfamily molecules MUC18/MCAM and ICAM-1 are associated with primary tumors and metastases. MUC18/MCAM expression confers metastatic potential and increased tumorigenicity to human melanoma cells. Expression of ICAM-1 has been shown to be a marker of poor prognosis in stage I tumors and interfering with its expression inhibits experimental metastasis by melanomas in nude mice. E-cadherin is used by epidermal melanocytes to interact with neighboring keratinocytes. Changes in E-cadherin expression and cellular localization is first observed in the radial growth phase, the earliest stage in melanoma development. Loss of E-cadherin function is associated with upregulation or induction of MUC18/MCAM and alpha v beta 3 in melanocytic cells in vitro and with alterations in the levels and cellular distribution of the transcriptional regulator beta-catenin in melanomas in vivo. These observations suggest that disturbances in E-cadherin function is not only important in carcinomas but may also be a critical event in melanoma tumor progression.
Cancer Metastasis Rev 1999
PMID:Cell adhesion molecules in the development and progression of malignant melanoma. 1072 89

Wnt signalling is involved in a variety of mammalian developmental processes, including cell proliferation, differentiation and epithelial-mesenchymal interactions, through which they contribute to the development of tissues and organs such as the limbs, the brain, the reproductive tract and the kidney. Wnts are secreted ligands that control cell processes via at least two pathways, one of which, the 'canonical' Wnt signalling pathway, operates through the cytosolic stabilisation of a transcriptional co-factor, beta-catenin. This is achieved by downregulating the activity of a beta-catenin turnover complex. Evidence from tumour expression studies, transgenic animals and in vitro experiments suggests that inappropriate activation of the canonical Wnt signalling pathway is a major feature in human neoplasia and that oncogenic activation of this pathway can occur at many levels. Inappropriate expression of the Wnt ligand and Wnt binding proteins have been found in a variety of human tumours. Further downstream, dysregulation of the beta-catenin turnover complex, by loss of the Adenomatous Polyposis Coli or Protein Phosphatase 2A proteins, or by activating mutations of beta-catenin, has been found in several tumour types, and is believed to be a key step in neoplastic progression. Transcriptional targets of the Wnt pathway include the cellular oncogenes cyclin D1 and c-myc. Activation of the Wnt signalling pathway by various means can therefore be a primary cause in oncogenesis, affecting cell proliferation, morphology and contact inhibition, as well as co-operating with other oncogenes in multistep tumour progression.
Cancer Metastasis Rev 1999
PMID:Wnt signalling in mammalian development and cancer. 1072 85

The Wnt signaling pathway functions reiteratively during animal development to control cell fate decisions. Inappropriate deregulation of this pathway leads to cancer in a number of tissues. The components that transduce the Wnt signal from the cell membrane to the cell nucleus are well conserved between vertebrates and Drosophila. A pivotal Wnt effector is the protein beta-catenin/Armadillo whose stability in the cytoplasm is low in unstimulated cells. Beta-catenin/Armadillo is targetted for proteasome-mediated degradation by a protein complex to which it binds. This complex consists of Axin, a putative scaffold protein which also binds to the tumor suppressor Adenomatous polyposis coli (APC) and glycogen synthase kinase 3 (GSK3)/Shaggy. Wnt signaling somehow inhibits the kinase activity of the quaternary complex. As a consequence, beta-catenin/Armadillo accumulates in the cytoplasm, translocates to the nucleus and becomes a transcriptional co-activator of T cell factor (TCF), the ultimate nuclear target of Wnt signaling. TCF is an architectural protein, mediating the assembly of multi-protein enhancer complexes. It cooperates with other enhancer-binding proteins and, together with beta-catenin/Armadillo, stimulates the transcription of Wnt target genes. Recently, repressors have been identified that prevent TCF from being active in the absence of Wnt signaling.
Cancer Metastasis Rev 1999
PMID:The control of beta-catenin and TCF during embryonic development and cancer. 1072 86

Development of effective chemopreventive agents for human consumption requires conclusive evidence of their efficacy in animal models that have relevance to human diseases. Transgenic adenocarcinoma mouse prostate (TRAMP) is an excellent model of prostate cancer that mimics progressive forms of human disease inasmuch as 100% of males develop histological PIN by 8-12 weeks of age that progress to adenocarcinoma with distant site metastases by 24-28 weeks of age. In these animals, ornithine decarboxylase (ODC) activity (>3-fold) as well as protein expression (>4-fold) was found to be markedly higher in the dorsolateral prostate as compared with the nontransgenic littermates, suggesting their suitability to determine the chemopreventive effect of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, against prostate cancer. Using male TRAMP mice, we studied the effect of oral consumption of DFMO on development of prostate carcinogenesis and surrogate end point biomarkers related to prostate cancer progression. In two independent experiments, each consisting of 8 animals on test, the cumulative incidence of prostatic cancer development at 28 weeks of age in 16 untreated TRAMP mice was 100% (16 of 16), whereas 94% (15 of 16) and 69% (11 of 16) of the animals exhibited distant site metastases to lymph nodes and lungs, respectively. Oral consumption of 1% DFMO (w/v) in the drinking water to TRAMP mice from 8 to 28 weeks of age resulted in a significant decrease in (a) weight (59%) and volume (66%) of prostate, (b) genitourinary weight (63%), and (c) ODC enzyme activity (52%) in the dorsolateral prostate. Importantly, in none of the DFMO-fed TRAMP mice were any distant metastases to lymph node and lungs observed. Furthermore, DFMO treatment resulted in the marked reduction in the protein expression of proliferation cell nuclear antigen, ODC, and probasin in the dorsolateral prostate. The protein expression of antimetastases markers, i.e., E-cadherin and alpha- and beta-catenin, was found to be restored in DFMO-fed animals as compared with the non-DFMO-fed mice. These chemopreventive effects of DFMO were further confirmed by immunohistochemical analysis of the dorsolateral prostate. Histological analysis of the dorsolateral prostate of DFMO-fed animals displayed marginal epithelial stratification, a small number of cribriform structures, elongated hyperchromatic epithelial nuclei, and a significant increase in apoptotic index. Non-DFMO-fed animals, on the other hand, displayed extensive epithelial stratification with profound cribriform structures accompanied with marked thickening, remodeling, and hypercellularity of the fibromuscular stroma. In nontransgenic littermates fed with DFMO, no significant alterations in the above parameters were evident. These data demonstrate that ODC represents a promising and rational target for chemoprevention of human prostate cancer and that TRAMP mice are excellent models for screening of novel drugs and chemopreventive regimens for potential human use.
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PMID:Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice. 1101 39

Primary pulmonary adenocarcinoma was studied, looking for relationships between the expression of cell adhesion molecules (CAMs) E-cadherin, beta-catenin and CD44v6, and clinicopathological tumour parameters and patient post-operative survival. Formalin-fixed, paraffin-embedded tissue from 120 primary lung adenocarcinomas, including 23 poorly differentiated tumours, 17 of probable bronchial origin, and 29 with a prominent bronchioloalveolar pattern, together with nodal metastatic tumour from 34 of these patients was stained using monoclonal antibodies and immunohistochemistry. Sections were scored either high level (>10% cells positive) or low level (<10% positive). High level expression of CD44v6 was retained in 28.4% (34/120) of tumours, while high levels of E-cadherin (57.5%, 69/120) and beta-catenin (80. 8%, 97/120) were more frequent. For all CAMs, staining levels did not correlate with nodal status, stage or tumour type. The apical or basal staining seen in normal bronchial and alveolar epithelium was often seen in papillary, glandular, and bronchioloalveolar areas of tumour, while solid invasive tumour more often showed pericellular staining. When the staining for each CAM in 34 nodal metastases was compared with that in the corresponding primary tumour, a high degree of concordance was found, with no tendency for metastases to show less staining than the primary tumour. Expression of E-cadherin and beta-catenin in the primary tumour had no influence on post-operative survival, but patients whose tumours had low level CD44v6 expression had a poorer post-operative survival than those with high levels of CD44v6 (p=0.0014 for all patients, p=0.0012 for stage I patients only). In primary pulmonary adenocarcinoma, the levels of expression of E-cadherin, beta-catenin, and CD44v6 are not associated with lymph node metastases or tumour stage but the staining pattern is associated with tumour morphology. Low levels of CD44v6 expression predict a poor post-operative survival, independently of stage, while there is no such relationship with the expression of E-cadherin or beta-catenin.
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PMID:Expression of CD44v6 but not E-cadherin or beta-catenin influences prognosis in primary pulmonary adenocarcinoma. 1111 58

Loss of E-cadherin and catenin expression may be associated with distant and lymph node metastases in breast cancer. Heterogeneity of E-cadherin expression is associated with poor prognosis, suggesting that E-cadherin and catenins may serve as useful prognostic markers for invasive breast carcinoma. Reduction or loss of expression of either E-cadherin or catenins is associated with invasion, metastasis and poor prognosis in several types of human malignancies. We investigated the expression of E-cadherin, and alpha- and beta-catenins by immunohistochemistry in 171 cases of primary invasive breast cancer, and compared the expression with clinicopathological parameters to define the relationship between expression and prognosis. E-cadherin immunoreactive protein was shown to be expressed in 97 cases. Reduction or lack of expression of E-cadherin was associated with distant metastasis. Based on immunohistochemical heterogeneity, E-cadherin-positive tumors were classified into heterogeneous, homogeneous and intermediate types. Interestingly, although patients with heterogeneous type demonstrated the lowest incidence of distant metastasis at diagnosis, they showed a higher incidence of subsequent distant metastasis, after surgery, and a lower survival rate than those with homogeneous type (p<0.05). E-cadherin expression was reduced or negative in metastatic axillary lymph nodes regardless of the expression in the primary tumor, suggesting that changes in E-cadherin expression are associated with not only distant metastasis but also lymph node metastasis. Tumors negative for either alpha- or beta-catenin expression demonstrated a higher incidence of distant metastasis than those expressing both catenins, suggesting that the expression of catenins is involved in breast cancer metastasis. Reduction or loss of E-cadherin and catenin expression may be associated with distant and lymph node metastases in invasive breast cancer, and the heterogeneous type may be associated with poor prognosis.
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PMID:The loss of E-cadherin, alpha- and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer. 1117 80


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