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

Dystroglycan (DG) is a single receptor that binds to multiple basement membrane proteins and forms a transmembrane link to the actin cytoskeleton. It was first isolated as a component of the dystrophin-glycoprotein complex, which plays a role in the maintenance of muscle cell integrity and is defective in many muscular dystrophies. Although studied most extensively in muscle tissues, DG is present at most cell-basement membrane interfaces, and only recently has investigation of DG functions in nonmuscle cells gained momentum. Information emerging from recent studies in epithelial cells is implicating DG in a wide range of critical cell responses to the basement membrane, ranging from organization of tissue architecture to cell survival. Moreover, DG functions appear to be frequently absent in carcinoma cells, implicating its loss in cancer progression. Although many questions remain as to its precise role in mammary tissue, DG is emerging as a potentially important player in mammary gland function.
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PMID:Dystroglycan: emerging roles in mammary gland function. 1498 37

Alterations in the basement membrane receptor dystroglycan (DG) are evident in muscular dystrophies and carcinoma cells and characterized by a selective loss or modification of the extracellular alpha-DG subunit. Defects in posttranslational modifications of DG have been identified in some muscular dystrophies, but the underlying modifications in carcinoma cells have not yet been defined. We reveal here multiple posttranslational modifications that modulate the composition and function of DG in normal epithelial cells and carcinoma cells. We show that alpha-DG is shed from the cell surface of normal and tumorigenic epithelial cells through a proteolytic mechanism that does not require direct cleavage of either alpha- or beta-DG. Shedding is dependent on metalloprotease activity and the proprotein convertase furin. Surprisingly, furin is also found to directly process alpha-DG as a proprotein substrate, changing the existing model of DG composition. We also show that the glycosylation of alpha-DG is altered in invasive carcinoma cells, and this modification causes complete loss of laminin binding properties. Together, these data elucidate several novel events regulating the functional composition of DG and reveal defects that arise during cancer progression, providing direction for efforts to restore this link with the basement membrane in carcinoma cells.
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PMID:Proteolytic enzymes and altered glycosylation modulate dystroglycan function in carcinoma cells. 1534 99

Dystroglycan (DG) is an adhesion molecule formed by two subunits, alpha (extracellular) and beta (transmembrane) DG, which are codified by a single gene and form a continuous link from the extracellular matrix to the intracellular cytoskeleton. Reduction or loss of expression of DG has been observed in human cancer cell lines and primary tumors and has been suggested to promote tumor development and invasiveness. In this study, the human breast epithelial non-tumorigenic MCF10F and the breast cancer MCF7 cell lines were engineered to stably express an exogenous DG cDNA and the effects on the phenotype of both cell lines were evaluated. The MCF10F transfected cells displayed an increased expression of both DG subunits which was associated with inhibition of the anchorage-dependent growth, accumulation of cells in the G0/G1 phase of the cell cycle and increased adhesion to a substratum. The MCF7 transfected cells were unable to restore alpha-DG despite an increased expression of the beta-DG subunit. Anchorage-dependent and independent growth and the in vivo tumorigenicity were reduced in these derivatives that also displayed a reduced adhesion to a substratum and were shown to release alpha-DG in the culture medium. These findings confirm and extend previous evidence that transformation of mammary epithelial cells is associated with loss of their ability to retain alpha-DG on the cell membrane. Moreover, they indicate that DG is involved in cell functions other than cell adhesion to the extracellular matrix, and that its loss of function might predispose to tumor progression by compromising regulatory controls over cell growth and proliferation.
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PMID:Increased expression of dystroglycan inhibits the growth and tumorigenicity of human mammary epithelial cells. 1566 32

Dystroglycan (DG), a non-integrin adhesion molecule, is a pivotal component of the dystrophin-glycoprotein complex, that is expressed in skeletal muscle and in a wide variety of tissues at the interface between the basement membrane (BM) and the cell membrane. DG has been mainly studied for its role in skeletal muscle cell stability and its alterations in muscular diseases, such as dystrophies. However, accumulating evidence have implicated DG in a variety of other biological functions, such as maturation of post-synaptic elements in the central and peripheral nervous system, early morphogenesis, and infective pathogens targeting. Moreover, DG has been reported to play a role in regulating cytoskeletal organization, cell polarization, and cell growth in epithelial cells. Recent studies also indicate that abnormalities in the expression of DG frequently occur in human cancers and may play a role in both the process of tumor progression and in the maintenance of the malignant phenotype. This paper reviews the available information on the biology of DG, the abnormalities found in human cancers, and the implications of these findings with respect to our understanding of cancer pathogenesis and to the development of novel strategies for a better management of cancer patients.
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PMID:The dystroglycan complex: from biology to cancer. 1592 Jul 57

Dystroglycan localizes to the basal domain of epithelial cells and has been reported to play a role in apical-basal polarity. Here, we show that Dystroglycan null mutant follicle cells have normal apical-basal polarity, but lose the planar polarity of their basal actin stress fibers, a phenotype it shares with Dystrophin mutants. However, unlike Dystrophin mutants, mutants in Dystroglycan or in its extracellular matrix ligand Perlecan lose polarity under energetic stress. The maintenance of epithelial polarity under energetic stress requires the activation of Myosin II by the cellular energy sensor AMPK. Starved Dystroglycan or Perlecan null cells activate AMPK normally, but do not activate Myosin II. Thus, Perlecan signaling through Dystroglycan may determine where Myosin II can be activated by AMPK, thereby providing the basal polarity cue for the low-energy epithelial polarity pathway. Since Dystroglycan is often downregulated in tumors, loss of this pathway may play a role in cancer progression.
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PMID:Dystroglycan and perlecan provide a basal cue required for epithelial polarity during energetic stress. 2889 30

The interaction between epithelial cells and the extracellular matrix is crucial for tissue architecture and function and is compromised during cancer progression. Dystroglycan is a membrane receptor that mediates interactions between cells and basement membranes in various epithelia. In many epithelium-derived cancers, beta-dystroglycan is expressed, but alpha-dystroglycan is not detected. Here we report that alpha-dystroglycan is correctly expressed and trafficked to the cell membrane but lacks laminin binding as a result of the silencing of the like-acetylglucosaminyltransferase (LARGE) gene in a cohort of highly metastatic epithelial cell lines derived from breast, cervical, and lung cancers. Exogenous expression of LARGE in these cancer cells restores the normal glycosylation and laminin binding of alpha-dystroglycan, leading to enhanced cell adhesion and reduced cell migration in vitro. Our findings demonstrate that LARGE repression is responsible for the defects in dystroglycan-mediated cell adhesion that are observed in epithelium-derived cancer cells and point to a defect of dystroglycan glycosylation as a factor in cancer progression.
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PMID:Loss of alpha-dystroglycan laminin binding in epithelium-derived cancers is caused by silencing of LARGE. 1924 52

During the last 15 years, following its identification and first detailed molecular characterization, the dystroglycan (DG) complex has taken centre stage in biology and biomedicine. Functions in different cells and tissues have been identified for this complex, ranging from its typical role in skeletal muscle as a sarcolemmal stabilizer, highlighted by the recently identified "secondary dystroglycanopathies", to a variety of very diverse functions including embryogenesis, cancer progression, virus particle entry and cell signalling. Such functional promiscuity can be in part explained when considering the multiple domain organization of the two DG subunits, the extracellular alpha-DG and the transmembrane beta-DG, that has been largely scrutinized, but only in part unraveled, exploiting a variety of recombinant and transgenic approaches. Herein, while rapidly recapitulating some of the functions that nowadays can be assigned safely to each DG domain, we also try to envisage a sort of worry list featuring and dwelling on some of the most compelling "mysteries" that should be solved to finally understand DG's functional diversity.
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PMID:Functional diversity of dystroglycan. 1930 39

The dystroglycanopathies are a group of inherited muscular dystrophies that have a common underlying mechanism, hypoglycosylation of the extracellular receptor alpha-dystroglycan. Many of these disorders are also associated with defects in the central nervous system and the eye. Defects in alpha-dystroglycan may also play a role in cancer progression. This review discusses the six dystroglycanopathy genes identified so far, their known or proposed roles in dystroglycan glycosylation and their relevance to human disease, and some of animal models now available for the study of the dystroglycanopathies.
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PMID:Abnormal glycosylation of dystroglycan in human genetic disease. 1953 54

Alpha-dystroglycan (alpha-DG) represents a highly glycosylated cell surface molecule that is expressed in the epithelial cell-basement membrane (BM) interface and plays an essential role in epithelium development and tissue organization. The alpha-DG-mediated epithelial cell-BM interaction is often impaired in invasive carcinomas, yet roles and underlying mechanisms of such an impaired interaction in tumor progression remain unclear. We report here a suppressor function of laminin-binding glycans on alpha-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, laminin-binding glycans are dramatically decreased, although the amount of alpha-DG and beta-dystroglycan is maintained. The decrease of laminin-binding glycans and consequent increased cell migration were associated with the decreased expression of beta3-N-acetylglucosaminyltransferase-1 (beta3GnT1). Forced expression of beta3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. beta3GnT1 was found to be required for laminin-binding glycan synthesis through formation of a complex with LARGE, thus regulating the function of LARGE. Interaction of the laminin-binding glycans with laminin and other adhesive molecules in BM attenuates tumor cell migratory potential by antagonizing ERK/AKT phosphorylation induced by the components in the ECM. These results identify a previously undescribed role of carbohydrate-dependent cell-BM interaction in tumor suppression and its control by beta3GnT1 and LARGE.
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PMID:Tumor suppressor function of laminin-binding alpha-dystroglycan requires a distinct beta3-N-acetylglucosaminyltransferase. 1958 35

The branching of complex N-glycans attached to growth factor receptors promotes tumor progression by prolonging growth factor signaling. The addition of the bisecting GlcNAc to complex N-glycans by Mgat3 has varying effects on cell adhesion, cell migration, and hepatoma formation. Here, we show that Chinese hamster ovary cells expressing Mgat3 and the polyoma middle T (PyMT) antigen have reduced cell proliferation and growth factor signaling dependent on a galectin lattice. The Mgat3 gene is not expressed in virgin mammary gland but is upregulated during lactation and is expressed in mouse mammary tumor virus (MMTV)/PyMT tumors. Mice lacking Mgat3 that cannot transfer the bisecting GlcNAc to N-glycans acquire PyMT-induced mammary tumors more rapidly and have an increased tumor burden, increased migration of tumor cells, and increased early metastasis to lung. Tumors and tumor-derived cells lacking Mgat3 exhibit enhanced signaling through the Ras pathway and reduced amounts of functionally glycosylated alpha-dystroglycan. Constitutive overexpression of an MMTV/Mgat3 transgene inhibits early mammary tumor development and tumor cell migration. Thus, the addition of the bisecting GlcNAc to complex N-glycans of mammary tumor cell glycoprotein receptors is a cell autonomous mechanism serving to retard tumor progression by reducing growth factor signaling.
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PMID:The bisecting GlcNAc on N-glycans inhibits growth factor signaling and retards mammary tumor progression. 2039 9


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