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

The cadherin/catenin complex, comprised of E-cadherin, beta-catenin and alpha-catenin, is essential for initiating cell-cell adhesion, establishing cellular polarity and maintaining tissue organization. Disruption or loss of the cadherin/catenin complex is common in cancer. As the primary cell-cell adhesion protein in epithelial cells, E-cadherin has long been studied in cancer progression. Similarly, additional roles for beta-catenin in the Wnt signaling pathway has led to many studies of the role of beta-catenin in cancer. Alpha-catenin, in contrast, has received less attention. However, recent data demonstrate novel functions for alpha-catenin in regulating the actin cytoskeleton and cell-cell adhesion, which when perturbed could contribute to cancer progression. In this review, we use cancer data to evaluate molecular models of alpha-catenin function, from the canonical role of alpha-catenin in cell-cell adhesion to non-canonical roles identified following conditional alpha-catenin deletion. This analysis identifies alpha-catenin as a prognostic factor in cancer progression.
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PMID:Bench to bedside and back again: molecular mechanisms of alpha-catenin function and roles in tumorigenesis. 1794 8

Molecular activities, regulating a balanced tissue organisation, are frequently disturbed during cancer progression. These include protein ectodomain shedding, a post-translational process that substantially changes the functional properties of the substrate protein. In comparison with normal epithelia, cancer cells almost invariably show diminished cadherin-mediated intercellular adhesion. This review will address cadherin ectodomain shedding and its functional consequence in normal physiology and in the tumor environment. Soluble cadherin fragments may retain specific biological activities during cancer cell invasion, angiogenesis and perineural invasion. When diffusion barriers disappear, soluble cadherins are detected in sera from cancer patients. Soluble N-(neural) cadherin may represent a novel diagnosis/prognostic biomarker showing a correlation with PSA in sera of prostate cancer patients. Furthermore, therapeutic monitoring in pancreas adenomacarcinoma revealed a correlation between circulating soluble N-cadherin and CA 19-9. A better understanding of cadherin regulation in cancer progression will likely increase our awareness of the importance of the combinatorial signals that regulate tissue integrity and eventually result in the identification of new therapeutics targeting cadherins.
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PMID:Soluble cadherins as cancer biomarkers. 1795 16

The signal transducer and activator of transcription-3 (STAT3) frequently activated during tumor progression has been linked to enhanced cell growth. In squamous cell carcinoma of the head and neck (HNSCC), STAT3 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways. In the present study, we have examined the potential mechanism by which cell-cell contact initiates STAT3 activation. Using a panel of HNSCC cell lines, Ca(+2)-dependent cell-cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of STAT3-Y705 and STAT1-Y701. This intercellular adhesion-induced STAT3 activation was mediated by JAK and Src signaling and partially by EGFR signaling. In addition, immunolocalization studies revealed initial formation of phosphorylated STAT3-Y705 at nascent E-cadherin cell junctions with eventual translocation to the nucleus in cell aggregates. Adhesion-mediated STAT activation in monolayer and cell aggregate cultures required functional E-cadherin. These results indicate that, in HNSCC cells, cadherin-mediated intercellular adhesion induces STAT signaling that may modulate cell survival and resistance to apoptosis during tumor progression.
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PMID:STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells. 1796 51

EPHA2 receptor tyrosine kinase is overexpressed in several human cancer types and promotes malignancy. However, the mechanisms by which EPHA2 promotes tumor progression are not completely understood. Here we report that overexpression of a wild-type EPHA2, but not a signaling-defective cytoplasmic truncation mutant (DeltaC), in human mammary epithelial cells weakens E-cadherin-mediated cell-cell adhesion. Interestingly, the total level of cadherins and the composition of the adherens junction complexes were not affected, nor was the tyrosine phosphorylation of the cadherin complex components changed. By contrast, RhoA GTPase activity was significantly affected by modulating the EPHA2 activity in MCF-10A cells. Treatment with a ROCK kinase inhibitor rescued cell-cell adhesion defects in EPHA2-overexpressing cells, whereas expression of constitutively activated Rho disrupted adherens junctions in DeltaC-expressing cells. EPHA2-dependent Rho activation and destabilization of adherens junctions appeared to be regulated via a signaling pathway involving Src kinase, low molecular weight phosphotyrosine phosphatase (LMW-PTP) and p190 RhoGAP. EPHA2 interacted with both Src and LMW-PTP, and the interactions increased in EPHA2-overexpressing cells. In addition, LMW-PTP phosphatase activity was elevated, and this elevation was accompanied by a decrease in tyrosine phosphorylation of p190 RhoGAP and destabilization of cell-cell adhesion. Expression of either a dominant negative LMW-PTP mutant, C12S, or a wild-type p190 RhoGAP rescued adhesion defects in EPHA2-overexpressing cells. Together, these data suggest that EPHA2 promotes tumor malignancy through a mechanism involving RhoA-dependent destabilization of adherens junctions.
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PMID:Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. 1819 90

Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-beta (TGF-beta), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor angiogenesis but also by enhancing tumor cell proliferation via the TGF-beta signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF-beta signaling. Our findings may have important implications for the clinical application of anti-VE-cadherin strategies.
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PMID:Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling. 1831 2

p120 catenin is a cadherin-associated protein that regulates Rho GTPases and promotes the invasiveness of E-cadherin-deficient cancer cells. Multiple p120 isoforms are expressed in cells via alternative splicing, and all of them are essential for HGF signaling to Rac1. However, only full-length p120 (isoform 1) promotes invasiveness. This selective ability of p120 isoform 1 is mediated by reduced RhoA activity, both under basal conditions and following HGF treatment. All p120 isoforms can bind RhoA in vitro, via a central RhoA binding site. However, only the cooperative binding of RhoA to the central p120 domain and to the alternatively spliced p120 N terminus stabilizes RhoA binding and inhibits RhoA activity. Consistent with this, increased expression of p120 isoform 1, when compared with other p120 isoforms, is predictive of renal tumor micrometastasis and systemic progression, following nephrectomy. Furthermore, ectopic expression of the RhoA-binding, N-terminal domain of p120 is sufficient to block the ability of p120 isoform 1 to inhibit RhoA and to promote invasiveness. The data indicate that the increased expression of p120 isoform 1 during tumor progression contributes to the invasive phenotype of cadherin-deficient carcinomas and that the N-terminal domain of p120 is a valid therapeutic target.
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PMID:A p120 catenin isoform switch affects Rho activity, induces tumor cell invasion, and predicts metastatic disease. 1840 99

Cadherin-mediated cell-cell adhesion defines the integrity of most tissues. Cell-cell adherens junctions are dynamic structures whose functional state is regulated by interactions of cadherin with beta-catenin, p120, and actin cytoskeleton structures. Small GTPases of the Rho family and GTPase Rap1 play the central role in the formation and maintenance of cell-cell adhesion. Aberrant activation of signaling pathways, transcriptional repression of the E-cadherin gene, ectopic expression of N-cadherin, and disturbances in regulation of adhesive and transcriptional functions of beta-catenin stimulate tumor progression.
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PMID:Changes in regulation of cell-cell adhesion during tumor transformation. 1870 82

Galectin-3 (Gal-3) is a beta-galactoside-binding protein that is involved in cancer progression and metastasis. Using a progressive human melanoma tissue microarray, we previously demonstrated that melanocytes accumulate Gal-3 during the progression from benign to dysplastic nevi to melanoma and further to metastatic melanoma. Herein, we show that silencing of Gal-3 expression with small hairpin RNA results in a loss of tumorigenic and metastatic potential of melanoma cells. In vitro, Gal-3 silencing resulted in loss of tumor cell invasiveness and capacity to form tube-like structures on collagen ("vasculogenic mimicry"). cDNA microarray analysis after Gal-3 silencing revealed that Gal-3 regulates the expression of multiple genes, including endothelial cell markers that appear to be aberrantly expressed in highly aggressive melanoma cells, causing melanoma cell plasticity. These genes included vascular endothelial-cadherin, which plays a pivotal role in vasculogenic mimicry, as well as interleukin-8, fibronectin-1, endothelial differentiation sphingolipid G-protein receptor-1, and matrix metalloproteinase-2. Chromatin immunoprecipitation assays and promoter analyses revealed that Gal-3 silencing resulted in a decrease of vascular endothelial-cadherin and interleukin-8 promoter activities due to enhanced recruitment of transcription factor early growth response-1. Moreover, transient overexpression of early growth response-1 in C8161-c9 cells resulted in a loss of vascular endothelial-cadherin and interleukin-8 promoter activities and protein expression. Thus, Gal-3 plays an essential role during the acquisition of vasculogenic mimicry and angiogenic properties associated with melanoma progression.
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PMID:Expression profiling of Galectin-3-depleted melanoma cells reveals its major role in melanoma cell plasticity and vasculogenic mimicry. 1898 6

alpha-Catenin is essential in cadherin-mediated epithelium development and maintenance of tissues and in cancer progression and metastasis. However, recent studies question the conventional wisdom that alpha-catenin directly bridges the cadherin adhesion complex to the actin cytoskeleton. Therefore, whether alpha-catenin plays a direct role in cadherin-dependent cell adhesion is unknown. Here, single-molecule force spectroscopy measurements in cells depleted of alpha-catenin or expressing the hereditary diffuse gastric cancer associated V832M E-cadherin germ-line missense mutation show that alpha-catenin plays a critical role in cadherin-mediated intercellular recognition and subsequent multibond formation within the first 300 ms of cell contact. At short contact times, alpha-catenin mediates a 30% stronger interaction between apposing E-cadherin molecules than when it cannot bind the E-cadherin-beta-catenin complex. As contact time between cells increases, alpha-catenin is essential for the strengthening of the first intercellular cadherin bond and for the ensuing formation of additional bonds between the cells, all without the intervention of actin. These results suggest that a critical decision to form an adhesion complex between 2 cells occurs within an extremely short time span and at a single-molecule level and identify a previously unappreciated role for alpha-catenin in these processes.
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PMID:{alpha}-Catenin mediates initial E-cadherin-dependent cell-cell recognition and subsequent bond strengthening. 1901 92

The mammary epithelium is thought to be stabilized by cell-cell adhesion mediated mainly by E-cadherin (E-cad). Here, we show that another cadherin, retinal cadherin (R-cad), is critical for maintenance of the epithelial phenotype. R-cad is expressed in nontransformed mammary epithelium but absent from tumorigenic cell lines. In vivo, R-cad was prominently expressed in the epithelium of both ducts and lobules. In human breast cancer, R-cad was down-regulated with tumor progression, with high expression in ductal carcinoma in situ and reduced expression in invasive duct carcinomas. By comparison, E-cad expression persisted in invasive breast tumors and cell lines where R-cad was lost. Consistent with these findings, R-cad knockdown in normal mammary epithelium stimulated invasiveness and disrupted formation of acini despite continued E-cad expression. Conversely, R-cad overexpression in aggressive cell lines induced glandular morphogenesis and inhibited invasiveness, tumor formation, and lung colonization. R-cad also suppressed the matrix metalloproteinase 1 (MMP1), MMP2, and cyclooxygenase 2 gene expression associated with pulmonary metastasis. The data suggest that R-cad is an adhesion molecule of the mammary epithelium, which acts as a critical regulator of the normal phenotype. As a result, R-cad loss contributes to epithelial suppression and metastatic progression.
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PMID:Loss of retinal cadherin facilitates mammary tumor progression and metastasis. 1949 Dec 71


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