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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because the cell adhesion molecule epithelial cadherin (E-cadherin) is absent in many invasive carcinomas, we transfected the E-cadherin gene into E-cadherin-negative, invasive breast cancer cell lines BT549 and HS578t to investigate the role of E-cadherin in invasive behavior. Although the transfected E-cadherin could mediate calcium-dependent aggregation to E-cadherin-transfected L-cells, morphology and invasiveness of the breast cancer cells were not altered. We investigated the strength of the linkage of the transfected E-cadherin to the actin cytoskeleton by examining the Triton X-100 solubility of the transfected E-cadherin. In BT549 and HS578t cells, a large proportion of the transfected E-cadherin was Triton soluble, whereas in E-cadherin-positive MCF-7 cells, Triton-insoluble E-cadherin was apparent at cell-cell borders. Interaction of E-cadherin with the actin cytoskeleton is thought to be mediated by the E-cadherin-binding proteins alpha-catenin, beta-catenin, and plakoglobin. We found normal levels of alpha-catenin and beta-catenin in BT549 and HS578t cells; however, low levels of plakoglobin were expressed in these cells compared to those found in weakly invasive MCF-7 cells. Furthermore, levels of tyrosine phosphorylation of beta-catenin were elevated in E-cadherin-transfected BT549 and HS578t cells compared to MCF-7 cells. We conclude that other factors such as the expression and appropriate posttranslational modification of cadherin-associated proteins must be in place for E-cadherin to be fully functional, i.e., to alter invasiveness. During cancer progression, loss of E-cadherin expression itself or multiple other mechanisms that lead to loss of cell-cell adhesion (mutation, loss of catenin expression, alterations in phosphorylation) may contribute to a more metastatic phenotype.
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PMID:Alterations in beta-catenin phosphorylation and plakoglobin expression in human breast cancer cells. 801 79

Alterations in the expression or function of molecules that affect cellular adhesion and proliferation are thought to be critical events for tumor progression. Loss of expression of the cell adhesion molecule E-cadherin and increased expression of the epidermal growth factor receptor are two prominent molecular events that are associated with tumorigenesis. The regulation of E-cadherin-dependent cell adhesion by epidermal growth factor (EGF) was therefore examined in the human breast cancer cell line, MDA-MB-468. In this study, changes were observed in the subcellular distribution of components that mediate the cytoplasmic connection between E-cadherin and the actin-based cytoskeleton in response to activation of the EGF receptor. Serum withdrawal activated E-cadherin-dependent cell-cell aggregation in MDA-MB-468 cells, and this treatment stimulated the interaction of actin, alpha-actinin, and vinculin with E-cadherin complexes, despite the absence of alpha-catenin in these cells. By contrast, the co-precipitation of actin with E-cadherin was not detected in several alpha-catenin positive epithelial cell lines. Treatment with EGF inhibited cellular aggregation but did not affect either the levels of E-cadherin or catenin expression nor the association of catenins (beta-catenin, plakoglobin/gamma-catenin, or p120(cas)) with E-cadherin. However, EGF treatment of the MDA-MB-468 cell line dissociated actin, alpha-actinin, and vinculin from the E-cadherin-catenin complex, and this coincided with a robust phosphorylation of beta-catenin, plakoglobin/gamma-catenin, and p120(cas) on tyrosine residues. Furthermore, inactivation of the EGF receptor in serum-treated MDA-MB-468 cells with either a function-blocking antibody or EGF receptor kinase inhibitors mimicked the effects of serum starvation by stimulating both cellular aggregation and assembly of E-cadherin complexes with vinculin and actin. These results demonstrate that the EGF receptor directly regulates cell-cell adhesion through modulation of the interaction of E-cadherin with the actin cytoskeleton and thus substantiates the coordinate role of both of these molecules in tumor progression and metastasis.
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PMID:The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton. 953 96

We are investigating the hypothesis that cancer progression involves the formation of abnormal cadherin-catenin complexes. The detailed analysis of cadherins and catenins expressed in a panel of 17 human bladder-cancer cell lines revealed that E-cadherin was down-regulated at the mRNA level in 5 cell lines. Interestingly, plakoglobin was also down-regulated at the mRNA level in these 5 cell lines only. Furthermore, a slower migrating form of pp120 was detected in these cell lines and in 2 cell lines with heterogeneous E-cadherin expression. Cloning of the cadherins expressed in the bladder lines revealed that P-cadherin is expressed in the lines expressing E-cadherin and down-regulated at the mRNA level in lines devoid of E-cadherin. N-cadherin was expressed in the 5 lines with reduced E-cadherin expression, in the 2 lines with heterogeneous E-cadherin expression and in 2 other cell lines. Thus, we showed that catenin changes occur in correlation with lack of E-cadherin expression and that N-cadherin becomes predominantly expressed in cells that have lost E-cadherin expression. Our data suggest that co-regulation of the expression of genes encoding different members of the classical cadherins occurs during tumor progression and that expression of some catenins is also coordinated with cadherin expression.
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PMID:Changes in cadherin-catenin complexes in the progression of human bladder carcinoma. 1036 Aug 23

Beta-catenin can play different roles in the cell, including one as a structural protein at cell-cell adherens junctions and another as a transcriptional activator mediating Wnt signal transduction. Plakoglobin (gamma)-catenin), a close homolog of beta-catenin, shares with beta-catenin common protein partners and can fulfill some of the same functions. The complexing of catenins with various protein partners is regulated by phosphorylation and by intramolecular interactions. The competition between different catenin partners for binding to catenins mediates the cross-talk between cadherin-based adhesion, catenin-dependent transcription and Wnt signaling. Although plakoglobin differs from beta-catenin in its functions and is unable to compensate for defects in Wnt signaling resulting from lack of beta-catenin, recent evidence suggests that plakoglobin plays a unique role in Wnt signaling that is different from that of beta-catenin. The functional difference between catenins is reflected in their differential involvement in embryonic development and cancer progression.
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PMID:Plakoglobin and beta-catenin: protein interactions, regulation and biological roles. 1095 12

beta-Catenin and its close homologue plakoglobin (gamma-catenin) are major constituents of submembranal cell-cell adhesion sites. In addition, beta-catenin is a key component in the canonical Wnt pathway. Aberrantly activated beta-catenin signaling contributes to cancer progression by inducing [in complex with lymphocyte enhancer factor (LEF)/T-cell factor (TCF)] the transcription of proliferation-related genes such as cyclin D1 and c-myc. Plakoglobin can also activate LEF/TCF-mediated transcription. Excessive beta-catenin signaling in MEF triggers a p53-mediated antiproliferative response by inducing the expression of ARF. We have demonstrated previously that plakoglobin also exerts a tumor-suppressive effect in certain cancer cell lines. To identify genes induced by beta-catenin and plakoglobin, DNA microarray analysis was carried out, and PML was among those genes of which the expression was significantly elevated by both plakoglobin and beta-catenin. Activation of the PML promoter by beta-catenin and plakoglobin was LEF/TCF-independent. We found that PML forms a complex with beta-catenin in cells, and the two proteins colocalize in the nucleus. In addition, PML, p300, and beta-catenin cooperated in transactivation of a subset of beta-catenin-responsive genes including ARF and Siamois but not cyclin D1. Retroviral expression of beta-catenin, plakoglobin, or PML suppressed the tumorigenicity of p53-negative human renal carcinoma cells, thus pointing to a novel antioncogenic response triggered by catenins that is mediated by the induction of PML.
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PMID:PML is a target gene of beta-catenin and plakoglobin, and coactivates beta-catenin-mediated transcription. 1238 61

Inactivation of the cadherin-mediated cell-cell adhesion system is believed to play a role in the initial steps of cancer invasion and metastasis. Expression of E-cadherin and its intracytoplasmic binding molecules (alpha-catenin, beta-catenin, and plakoglobin) was examined immunohistochemically in 84 cases of intrabronchial precancerous lesions (bronchial squamous metaplasia (BSM) without atypia, BSM with atypia, dysplasia), and 21 cases of carcinoma in situ, and 4 cases of microinvasion to the bronchial wall, and 32 cases of stage I well differentiated squamous cell carcinoma (squamous cell carcinoma) to investigate the association between expression of E-cadherin and/or catenins and cancer progression. Reduced expression of E-cadherin and/or catenins was closely correlated with an atypical grade of dysplasia in the basal layer (p<0.05). In particular, downregulation of E-cadherin and/or catenins was associated with an atypical grade of BSM with atypia in intrabronchial lesions (p<0.01). We conclude that downregulation of alpha-catenin and/or beta-catenin, which may reflect dysfunction of the cadherin-mediated cell-cell adhesion system, is an important marker for atypical grade during carcinogenesis of the bronchial epithelium.
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PMID:Frequent loss of E-cadherin and/or catenins in intrabronchial lesions during carcinogenesis of the bronchial epithelium. 1589

Our laboratory has shown that vascular endothelial growth factor receptor-1 (VEGFR-1) expression on human pancreatic cancer cell lines mediates cell migration and invasion. Because epithelial to mesenchymal transition (EMT) also plays a role in cell motility by altering the cell phenotype and morphology, we hypothesized that VEGFR-1 activation induces molecular alterations that mediate EMT. Our treatment of the human pancreatic cancer cell line L3.6pl with the VEGFR-1 ligands VEGF-A and VEGF-B led to morphologic changes characteristic of EMT, including loss of polarity, increased intercellular separation, and the presence of pseudopodia. Immunofluorescent staining with antibodies to E-cadherin and beta-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and beta-catenin from their usual cell membrane-bound location to the cytoplasm and nucleus, respectively. Western blotting showed that VEGFR-1 activation led to decreased expression of the epithelial markers E-cadherin and plakoglobin, increased expression of the mesenchymal markers vimentin and N-cadherin, and increased nuclear expression of beta-catenin. Pretreatment of tumor cells with a VEGFR-1 blocking antibody inhibited the VEGFR-1-induced immunohistochemical and molecular changes in E-cadherin. VEGFR-1 activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug. The changes mediated by VEGFR-1 in this pancreatic carcinoma cell line are highly consistent with the changes characteristic of EMT. Given our previous finding of VEGFR-1-mediated tumor cell invasion and migration in pancreatic carcinoma cells, we hypothesize that VEGFR-1 plays a role in tumor progression in pancreatic cancer through the induction of EMT.
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PMID:Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. 1639 14

Gamma-catenin (plakoglobin) exists in cells either as a component of adherens junctions, along with beta-catenin and alpha-catenin, or in association with desmoplakin in desmosomes, which are in turn coupled to the cytoskeleton linking to the plasma membrane. Although gamma-catenin overexpression is observed in many cancers, the molecular basis of its contribution to tumor progression remains unclear. In this study, we examined gamma-catenin overexpression-mediated effects leading to altered regulation of effector genes such as PTTG and c-Myc, as well as differential activation of signaling pathways. We found that overexpression of gamma-catenin caused: (1) a reduction in E-cadherin and corresponding increase in vimentin levels concomitant with increased cell mobility and migration; (2) enhancement in the levels of phosphorylated Akt and Erk in the presence of EGF and (3) an increase in PTTG and c-Myc protein levels, which are likely to accelerate chromosomal instability and uncontrolled proliferation, respectively, in the affected cells. These effects resulting from overexpression of gamma-catenin were further validated in converse experiments with the aid of siRNA knockdown of the endogenous gamma-catenin gene. In conclusion, our studies provide a molecular basis for the promotion of genomic instability and the oncogenic effects due to overexpression of gamma-catenin in human cancer.
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PMID:Aberrant activation of gamma-catenin promotes genomic instability and oncogenic effects during tumor progression. 1824 58

Latent membrane protein-1 (LMP1) is considered the major oncoprotein of Epstein-Barr virus and is frequently expressed in nasopharyngeal carcinoma (NPC). LMP1 promotes growth and migration of epithelial cells, and the loss of plakoglobin has been identified as a contributing factor to LMP1-induced migration. Plakoglobin is a junctional protein that can also serve as a transcription factor in Tcf/Lef signaling. To determine the effects of LMP1 on the molecular and functional properties of plakoglobin, LMP1 was overexpressed in the NPC cell line C666-1. LMP1 did not affect plakoglobin stability but did decrease plakoglobin transcription. The resultant decreased levels of nuclear plakoglobin did not affect Tcf/Lef activity or the amount of plakoglobin bound to Tcf4. Although LMP1 induced and stabilized beta-catenin, a protein with common binding partners to plakoglobin, the loss of plakoglobin did not affect its association with Tcf4. However, LMP1 did induce a cadherin switch from E- to N-cadherin, a process involved in cancer progression, and enhanced the association of junctional beta-catenin with N-cadherin. LMP1 decreased overall levels of junctional plakoglobin but the remaining junctional plakoglobin was found associated with the induced N-cadherin. This increased association of junctional plakoglobin with N-cadherin was a distinguishing feature of LMP1-expressing cells that have reduced migration due to restoration of plakoglobin. Low levels of plakoglobin were also detected in human NPC tissues. These findings reveal that the effects of LMP1 on junctional plakoglobin and the initiation of a cadherin switch likely contribute to metastasis of NPC.
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PMID:Epstein-Barr virus latent membrane protein-1 effects on junctional plakoglobin and induction of a cadherin switch. 1958 75

The ability of cells to modulate interactions with each other and the substrate is essential for epithelial tissue remodeling during processes such as wound healing and tumor progression. However, despite strides made in the field of proteomics, proteins involved in adhesion have been difficult to study. Here, we report a method for the enrichment and analysis of proteins associated with the basal surface of the cell and its underlying matrix. The enrichment involves deroofing the cells with 20 mM ammonium hydroxide and the removal of cytosolic and organellar proteins by stringent water wash. Proteomic profiling was achieved by LC-FTMS, which allowed comparison of differentially expressed or shared proteins under different cell states. First, we analyzed and compared the basal cell components of mouse keratinocytes lacking the cell-cell junction molecule plakoglobin with their control counterparts. Changes in the molecules involved in motility and invasion were detected in plakoglobin-deficient cells, including decreased detection of fibronectin, integrin beta(4), and FAT tumor suppressor. Second, we assessed the differences in basal cell components between two human oral squamous cell carcinoma lines originating from different sites in the oral cavity (CAL33 and UM-SCC-1). The data show differences between the two lines in the type and abundance of proteins specific to cell adhesion, migration, and angiogenesis. Therefore, the method described here has the potential to serve as a platform to assess proteomic changes in basal cell components including extracellular and adhesion-specific proteins involved in wound healing, cancer, and chronic and acquired adhesion-related disorders.
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PMID:Detection of differentially expressed basal cell proteins by mass spectrometry. 1995 77


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