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)

Src has been implicated in the development and progression of human colon cancer. Because the capacity for tumor cells to dissociate from the primary tumor is a critical step in the development of metastases, the effect of a naturally occurring, activated Src-531 on intercellular adhesion was examined. Homotypic adhesion was assessed using dissociation assays on Src-transformed rat fibroblasts and human colon cancer cell lines. The data indicate that both rodent and human cells expressing the mutant Src protein display up to 7-fold less homotypic adhesion than do wild-type cells (P < 0.01). Experiments demonstrated that cadherin was phosphorylated in cells transfected with activated Src and that cadherin/catenin complexes were disrupted as a result. Experiments using dominant negative (DN) Src or an Src-specific inhibitor (PD 180970), demonstrated that adhesion was restored when Src activity was inhibited in Src-531 transfectants, confirming that Src is a causal factor in the decreased homotypic adhesion observed. In addition, DN Ras, DN focal adhesion kinase (FAK), but not Stat3beta, restored intercellular adhesion, which suggested that Ras and FAK may be downstream effectors of Src-mediated homotypic adhesion. Collectively, these data support a role for Src, Ras, and FAK in the regulation of intercellular adhesion, which may in turn regulate metastatic potential of human colon cancer cells.
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PMID:Increased Src activity disrupts cadherin/catenin-mediated homotypic adhesion in human colon cancer and transformed rodent cells. 1198 Jun 66

Inflammatory breast carcinoma (IBC) is characterized by florid tumor emboli within lymphovascular spaces termed lymphovascular invasion (LVI). Using a human-scid model of IBC (MARY-X), we have demonstrated using retrovirally-mediated dominant-negative E-cadherin mutant approaches (H-2K(d)-E-cad), that the tumor cell embolus (IBC spheroid) forms on the basis of an intact and overexpressed E-cadherin/alpha, beta-catenin axis which mediates tumor cell-tumor cell adhesion analogous to the embryonic blastocyst and accounts for the compactness of the embolus. The tumor cell embolus (IBC spheroid), in contrast, fails to bind the surrounding vascular endothelial cells both in vitro and in vivo because of markedly decreased sialyl-Lewis X/A carbohydrate ligand-binding epitopes on its overexpressed MUC1 which are necessary for binding endothelial cell E-selectin. This tumor cell-endothelial cell aversion further contributes to the compactness of the IBC spheroid and its passivity in metastasis dissemination. This passivity is manifested by a dramatic increase in metastatic pulmonary emboli following palpation of the primary tumor. In assessing this passivity of metastatic dissemination, we compared the effects of palpation on MARY-X with the effects of palpation on a derived dominant-negative E-cadherin mutant (H-2K(d)-E-cad), as well as other well known human tumoral xenografts exhibiting no (MCF-7, T47D), low (MDA-MB-231, MDA-MB-468) or high (C8161, M24(met)) levels of spontaneous metastasis but no LVI. Palpation of each xenograft similarly increased intratumoral pressure by 200% (10-->30 mmHg) but dramatically increased the numbers and sizes of pulmonary metastases 10-100-fold (P<0.001) only in MARY-X. The mechanism of this effect was through an immediate post-palpation release of circulating tumor emboli detected 2-3 min after palpation (P<0.01) by human cytokeratin 19 RT-PCR of extracted RNA from 300 microl of murine blood. Although circulating human tumor cell-derived growth factors (IGF-I, IGF-II, TGF-alpha and TGF-beta) and angiogenic factors (VEGF and bFGF) were detected by ELISA in murine serum of MARY-X, palpation did not further increase the circulating levels of these factors (P>0.1). Our findings support the cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in IBC.
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PMID:Cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in inflammatory breast carcinoma. 1203 65

Snail is a zinc finger transcription factor that triggers the epithelial-mesenchymal transition (EMT) by directly repressing E-cadherin expression. Snail is required for mesoderm and neural crest formation during embryonic development and has recently been implicated in the EMT associated with tumour progression. In a series of human breast carcinomas, we have analysed the expression of Snail and that of molecules of the E-cadherin/catenin complexes. We have also correlated these data with the pathological features of the tumours. We show that Snail expression inversely correlates with the grade of differentiation of the tumours and that it is expressed in all the infiltrating ductal carcinomas (IDC) presenting lymph node metastases that were analysed. In addition, Snail is expressed in some dedifferentiated tumours with a negative nodal status. Considering that Snail is involved in the induction of the invasive and migratory phenotype in epithelial cells, these results indicate that it is also involved in the progression of breast ductal tumours, where it could additionally serve as a marker of the metastatic potential.
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PMID:Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. 1208 40

Associated with the metastatic progression of epithelial tumors is the dynamic regulation of cadherins. Whereas E-cadherin is expressed in most epithelium and carcinomas, recent studies suggest that the up-regulation of other cadherin subtypes in carcinomas, such as N-cadherin, may function in cancer progression. We demonstrate that a signal transduction cascade links the N-cadherin.catenin adhesion complex to up-regulation of the anti-apoptotic protein Bcl-2. In suspension, aggregates of DU-145 cells, an E-cadherin expressing human prostate carcinoma line, survive loss of integrin-dependent adhesion by a different anti-apoptotic signaling pathway than the N-cadherin expressing lines PC3 and PC3N. N-cadherin intercellular adhesion mediates a 3.5-fold increase in Bcl-2 protein expression, whereas the level of the proapoptotic protein Bax remains constant. Only N-cadherin ligation in PC3 cells, which express both N-cadherin and E-cadherin, is sufficient to induce activation of Akt/protein kinase B. N-cadherin homophilic ligation initiates phosphatidylinositol 3-kinase-dependent activation of Akt resulting in Akt phosphorylation of Bad on serine 136. Following N-cadherin homophilic adhesion phosphatidylinositol 3-kinase was identified in immunoprecipitates of the N-cadherin.catenin complex. The recruitment of phosphatidylinositol 3-kinase to the adhesion complex is dependent on ligation of N-cadherin and an organized actin cytoskeleton because cytochalasin D blocks the recruitment. We propose that N-cadherin homophilic adhesion can initiate anti-apoptotic signaling, which enhances the Akt cell survival pathway in metastatic cancer.
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PMID:Signal transduction from N-cadherin increases Bcl-2. Regulation of the phosphatidylinositol 3-kinase/Akt pathway by homophilic adhesion and actin cytoskeletal organization. 1209 80

Multi-cellular spheroids (MCS) generated from tumor cells serve as excellent in vitro models for understanding the mechanisms of tumor progression and micro-metastasis. We have compared the expression of molecular markers with reference to their growth as conventional adherent monolayers (2-D) and anchorage independent cultures (3-D) using two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines differed in their ability to form spheroids with respect to their aggregation potential, with B16F10 forming large clusters compared to Clone M3. A panel of molecular markers comprising cell adhesion molecules, cyclin dependent kinase inhibitors and members of the cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D cultures. There was a distinct difference in the patterns of expression of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells grown as monolayers in both cell lines. Also, there was an increase in cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10 cell line. The expression of alpha and gamma catenin was down regulated in spheroids. As these molecules are implicated in the regulation of cell proliferation, alterations in the expression of these molecules in 3-D cultures compared to their 2-D counterparts suggests the importance of spheroids as experimental model for tumorigenesis.
Clin Exp Metastasis 2002
PMID:Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. 1219 73

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

In recent years there has been a trend towards conservative management of uveal melanoma (UM), aimed at preserving the eye and vision. Despite improvements with this approach, recurrent tumour and metastatic disease still occur, and the management remains problematic. As a result of these limitations, there is interest in gaining a greater understanding of molecular changes associated with aggressive disease patterns in UM. This might result in new, more effective and less toxic therapies as well as provide prognostic information for defining subgroups of patients with a less favourable prognosis as potential candidates for adjuvant therapies. Accumulating evidence over the past decade suggests that disturbance in the cadherin-catenin adhesion complex is critical in the process leading to invasion and metastasis of many cancers. The recent advent of DNA micro-array technology now offers an unprecedented ability to study these molecules and others associated with malignant transformation. In this mini-review, the aspects of tumour progression in which cadherin-catenin may be involved are dealt with along with the potential application of DNA micro-array technology to the problem in UM.
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PMID:Biomolecular markers of malignancy in human uveal melanoma: the role of the cadherin-catenin complex and gene expression profiling. 1256 77

Wilms' tumour is a pediatric neoplasm exhibiting histologic features of developing kidney. Although the majority of Wilms' tumour patients are treated effectively, approximately 15% develop metastases and of these, 30% succumb to their disease. The biologic factors governing Wilms' tumour metastasis are largely unknown. Attempts at deriving representative Wilms' tumour cell lines, which could facilitate functional studies, have only been partially successful thus far. We now report on derivation and characterization of a Wilms' tumour cell line, WiT 49, from a first-generation xenograft of a human Wilms' tumour lung metastasis. WiT 49 recapitulates the phenotype of the parent tumours (primary and lung metastasis) and expresses normal WT1, overexpresses IGFII and carries a frequently identified p53 mutation. We recently reported overexpression of hepatocyte growth factor(HGF) and its receptor met in a series of Wilms' tumours with higher levels in homotypic metastatic cases. We therefore examined WiT 49 for expression of HGF/met and for met signaling targets associated with cell adhesion and cytoplasmic mediators of transcription using Western blot, co-immunoprecipitation, immunofluorescence labeling and zymography. Our results show co-expression of HGF and met protein, absence of E-cadherin, high levels of beta-catenin co-immunolocalized to met at the cell membrane and moderate levels of gamma-catenin and ezrin protein expression. After cell fractionation, beta-catenin was detected in the cytoplasm and nuclei of WiT 49 with relatively higher levels in the cytoplasm as compared to nuclei. Examination of MMP expression in WiT 49 showed constitutive activation of MMP 9 and latent MMP 2 supporting possible beta-catenin-mediated transcriptional activation. The WiT 49 cell line responded to recombinant human HGF by an increase in the expression of the met receptor, recruitment of the Gab-1 adapter protein to met and release of bound beta-catenin from met. Our studies therefore establish WiT 49 as a representative Wilms' tumour cell line derived from a lung metastasis that co-expresses HGF/met and shows absence of the cadherin-catenin complex supporting a role for these factors in regulation of the invasive and metastatic phenotype in Wilms' tumour.
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PMID:Derivation and characterization of a Wilms' tumour cell line, WiT 49. 1450 35

Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and spread to cervical lymph nodes, with distant metastases developing in 30-40% of cases. HPV-16 is an important risk factor for HNSCC. How HPV enhances susceptibility to HNSCC is not fully understood, but seems to involve cofactors. In this study, we examined the effect of the cooperation between HPV-16 and the tyrosine kinase receptor ErbB-2 on E-cadherin/catenin complex patterns and neoplastic transformation of human normal oral epithelial (NOE) cells. We report that overexpression of ErbB-2 or E6/E7 alone does not affect E-cadherin/catenin complex patterns nor does it induce cell transformation of NOE cells. In contrast, coexpression of E6/E7 and ErbB-2 downregulates E-cadherin and catenin expression. This is accompanied by cytoplasmic localization of E-cadherin, as well as nuclear translocation of alpha, beta, and gamma-catenins. Furthermore, we demonstrate that E6/E7 cooperate with overexpressed ErbB-2 to induce tumor formation in nude mice and to upregulate cyclin D1 and c-myc expression. Our data suggest that E6/E7 cooperate with ErbB-2 in head and neck carcinogenesis, at least in part, via the conversion of beta-catenin from a cell adhesion to a nuclear function, that is, to act as a potential transcriptional regulator. This conversion leads to the upregulation of cyclin D1, c-myc and other oncoproteins necessary for alteration of the E-cadherin/catenin complex and cell transformation of NOE cells.
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PMID:E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. 1472 63

Metastases of various malignancies have been shown to be inversely related to the abundance of nm23 protein expression. However, the downstream pathways involved in nm23-mediated suppression of metastasis have not been elucidated. In the present investigation, we used cDNA microarrays to identify novel genes and functional pathways in nm23-mediated spontaneous breast metastasis. Microarray experiments were performed in a pair of cell lines, namely, C-100 (only vector transfected; highly metastatic) and H1-177 (nm23 transfected; low metastatic), derived from human mammary carcinoma cell line MDA-MB-435. The cDNA microarray analysis using GeneSpring software revealed significant as well as consistent alterations in the expression (up- and downregulation) of 2158 genes in a total of 18889 genes between high and low metastatic cells. Some of these genes were grouped into 6 functional categories, namely, invasion and metastasis, apoptosis and senescence, signal transduction molecules and transcription factors, cell cycle and repair, adhesion, and angiogenesis to extrapolate an association between these genes and different functional pathways involved in nm23-regulated metastasis. The results suggest that nm23 gene plays a major role in metastasis and its mechanism of action of metastasis suppression may involve downregulation of genes associated with cell adhesion, motility (integrins alpha2, -8, -9, -L and -V, collagen type VIII alpha1, fibronectin 1, catenin, TGF-beta2, FGF7, MMP14 and 16, ErbB2) and possibly certain tumor/metastasis suppressors (2 members of SWI/SNF-related matrix-associated proteins 2 and 5 and PTEN).
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PMID:Expression profile of genes associated with antimetastatic gene: nm23-mediated metastasis inhibition in breast carcinoma cells. 1473 69


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