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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible mitogenic activity of fibronectin (FN) in human primary and metastatic melanoma lines and clones and the involvement of integrins in mediating this effect were evaluated. Quescent human melanoma cells cultured in serum-free medium proliferated in a dose- and time-dependent fashion to immobilized FN as indicated by [3H]thymidine incorporation, increment of cell number, and cell cycle analysis. This response to FN was observed with tumor clones isolated from a subcutaneous metastasis and with primary or metastatic melanomas from different patients, but only when tumor cells expressed the alpha 5 subunit of the FN receptor (i.e., VLA-5). Proliferation to FN by a primary tumor (Me4405) expressing all FN receptors and by a tumor clone (2/60) lacking only the alpha 4 subunit was inhibited by monoclonal antibodies to the alpha 5 and beta 1 but not by monoclonal antibodies to other subunits of FN receptors. Mapping of FN regions responsible for the proliferative signal was performed by stimulating melanoma cells with different FN proteolytic fragments and indicated that a significant mitogenic signal was provided by the M(r) 120,000 alpha-chymotrypsin fragment containing the Arg-Gly-Asp sequence. The proliferation of melanoma cells to FN and to FN fragments was also significantly inhibited by peptides containing the Arg-Gly-Asp sequence. These data indicate that FN can stimulate the proliferation of quiescent melanoma cells and that integrins as alpha 5 beta 1 are involved in the response of tumor cells to this extracellular matrix protein.
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PMID:Role of the alpha 5 beta 1 integrin receptor in the proliferative response of quiescent human melanoma cells to fibronectin. 138 57

To resist substantial wall shear stress (WSS) exerted by flowing blood, metastatic melanoma cells can form adhesive contacts with subendothelial extracellular matrix proteins, such as fibronectin (FN). Such contacts may be stabilized by transglutaminase catalyzed-cross-linkage of cell focal adhesion proteins. We analyzed human melanoma cell adhesion under flow by decreasing the flow (WSS) of melanoma cell suspensions and allowing them to adhere to immobilized wheat germ agglutinin or FN. At the wall shear adhesion threshold (WSAT), cell adherence was rapid with no rolling. Following cell adherence, we increased the flow and determined the wall shear detachment threshold (WSDeT). Cells spread and remained adherent on immobilized FN at high WSDeTs (greater than or equal to 32.5 dynes/cm2). The high resistance of adherent cells to shear forces suggested that transglutaminase-mediated crosslinking might be involved. Transglutaminase inhibitors monodansylcadaverine and INO-3178 decreased WSAT, and at low concentrations completely inhibited tumor cell spreading and promoted detachment at low WSDeTs (0.67 dynes/cm2). In static adhesion assays, transglutaminase inhibitors decreased cell adhesion to immobilized-FN in a dose-dependent manner and prevented the formation of crosslinked 125I-FN complex that failed to enter a SDS-polyacrylamide gradient gel. The data suggest that transglutaminase-catalyzed crosslinking, particularly in the presence of WSS, may be important in stabilizing cellular adhesive contacts during adhesion to immobilized-FN.
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PMID:Transglutaminase stabilizes melanoma adhesion under laminar flow. 172 25

Antigen expression was studied by immunohistochemistry in 133 human melanocytic skin lesions to gain insight into the initial steps of tumor development, i.e. in particular the change from melanocytes to benign nevi. We refer to the proposed progression model of Clark and co-workers. The following types of antigens were investigated: (i) intermediate filament antigens (vimentin), (ii) melanoma-associated antigens (HMB-45, NKI/C3, MA-930, LS59), (iii) proliferation-associated antigens (S-100, Ki67, Ro/SSA, calmodulin), (iv) progression-associated antigens (HLA-DR, ICAM-1), and (v) basal membrane antigens (bullous pemphigoid antigen, laminin, fibronectin, collagen type IV). The intensity of expression and the topography of immunoreactive pigment cells were compared with the stage of tumor progression. Special attention was paid to the early steps of this process, i.e. the disturbance of the epidermal melanin unit and the development of melanocytic ("nevocellular")nevi. A dramatic shift of antigen expression (antigen types [i] to [v]) was noted in benign nevi compared with melanocytes. Nevi with cellular atypia disclosed a tendency towards an increased percentage of tumor cells reactive for melanoma- and progression-related antigens (types [ii] and [iv]). However, there was no clear cut level of distinction of antigen expression (types [i] to [v]) between benign and primary malignant melanocytic tumors. So-called dysplastic nevi resembled benign tumors or melanocytes rather than malignant melanoma. Metastatic melanoma of skin showed a relatively high number of Ki67-positive, cycling melanoma cells. The results have a bearing on the concepts of melanocytic nevus ontogenesis and "maturation". It appears that melanocytes lose maturity on their way down to the dermis in contrast to traditional concepts (Abtropfung); this might be of importance for our understanding of melanoma development in association with melanocytic nevi. Our findings are discussed with regard to Clark's model of tumor progression.
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PMID:The initial steps of tumor progression in melanocytic lineage: a histochemical approach. 174 97

Expression of alpha and beta subunits of VLA and VNR integrins was analyzed by cytofluorimetric analysis on 6 different human primary and metastatic melanoma cell cultures. Marked inter-tumor heterogeneity was observed, and expression of VLA-alpha I, VLA-alpha 2 and VLA-alpha 6 was lower on primary melanomas than on metastatic lesions. The function of VLA products on melanoma cells was assessed by adhesion assays to extracellular matrix (ECM) proteins using a panel of melanoma clones previously characterized for the presence and heterogeneity of expression of the distinct VLA-alpha subunits. These experiments indicated that intra-tumor heterogeneity in the integrin profile can influence the interaction of neoplastic cells with ECM proteins. Inhibition of adhesion with antibodies to VLA-alpha subunits revealed that the presence on melanoma cells of VLA-alpha 2, VLA-alpha 5 and VLA-alpha 6 is relevant for the adhesion to type-IV collagen, fibronectin and laminin respectively. Culture of tumor cells in the presence of cytokines such as rIL-I beta, rTNF-alpha, rIFN-gamma or TGF-beta I could induce up- or down-modulation in the level of expression of multiple VLA integrins. Cytokine-mediated antigenic shifts in the VLA profile of melanoma cells were detected by cytofluorimetric analysis as early as 24 hr after cytokine exposure. The cytokine-dependent change in the matrix receptor profile of melanoma cells also affected the adhesion to ECM proteins as revealed by the enhanced adhesion of rTNF-alpha-treated cells to fibronectin. These data indicate that constitutive heterogeneity in the integrin profile or cytokine-mediated shifts in VLA expression can affect the ability of human melanoma cells to interact with different ECM components.
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PMID:Heterogeneity for integrin expression and cytokine-mediated VLA modulation can influence the adhesion of human melanoma cells to extracellular matrix proteins. 199 84

Tumor cell metastasis involves a complex series of interdependent events, including repeated invasion of basement membranes. Studies from several laboratories have implicated tumor cell adhesion and migration in response to laminin as a major contributing factor in tumor cell invasion. The current studies address the direct role of type IV collagen in promoting tumor cell adhesion, spreading, and migration. The observations of type IV collagen-mediated cellular behavior are contrasted with cellular behavior on type I collagen. The highly metastatic K1735 M4 melanoma cell line adhered, spread, and migrated in response to type IV collagen in a concentration-dependent manner. Functional assays using well-defined proteolytic fragments of type IV collagen demonstrated that melanoma cells interact with multiple domains of this protein. Highly metastatic melanoma cells adhered, spread, and exhibited motile behavior in response to 0.2 to 200 nM concentrations of a purified pepsin-generated, triple helix-rich domain of type IV collagen. In contrast, cells adhered and spread but were essentially nonmotile in response to a purified major noncollagenous domain of the protein. In addition, de novo protein synthesis was required for cell adhesion to the major noncollagenous domain, whereas adhesion to the helical domain was less dependent upon de novo protein synthesis. Arg-Gly-Asp (RGD)-related peptides were used to study the adhesion and spreading of melanoma cells on type IV collagen. The results demonstrated that a serine containing RGD-related peptide (GRGDSP) has virtually no effect on melanoma cell adhesion on type IV collagen-coated substrata, whereas this peptide inhibited melanoma cell adhesion to fibronectin-coated substrata in a concentration-dependent manner. In contrast, when threonine was substituted for serine (GRGDTP), cell adhesion to type IV collagen was significantly (45%) inhibited. The threonine-containing peptide virtually eliminated cell adhesion on substrata coated with type I collagen. These data demonstrate that adhesion, spreading, and migration of melanoma cells on type IV collagen have a complex molecular basis which is partially dependent on RGD-related sequences.
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PMID:Type IV collagen-mediated melanoma cell adhesion and migration: involvement of multiple, distinct domains of the collagen molecule. 275 12

The migration of tumor cells through basement membranes and extracellular matrices is an integral component of tumor invasion and metastasis. Laminin and fibronectin are two basement membrane- and extracellular matrix-associated noncollagenous glycoproteins that have been shown to promote both cell adhesion and motility. Purified preparations of laminin and fibronectin stimulated the directed migration of B16 murine metastatic melanoma cells in vitro as assessed in modified Boyden chambers. The stimulation of migration occurred over a concentration range of 1-100 micrograms/ml of laminin or fibronectin, with a peak response occurring between 12.5 and 25 micrograms/ml. The maximal response of these cells was 80-120-fold higher than control migration. Affinity-purified antibody preparations specifically abrogated the migration of these cells in response to the respective proteins. Tumor cells in suspension were preincubated in physiologic levels of plasma fibronectin prior to assay to partially mimic what occurs when a metastasizing cell is in the blood stream. This preincubation with plasma fibronectin had no effect on the subsequent migration of cells in response to either laminin or fibronectin. Furthermore, experiments using filters precoated with fibronectin or laminin indicated that these cells could migrate by haptotaxis to these two proteins. We conclude that tumor cell migration in response to such noncollagenous adhesive glycoproteins could be an important aspect in the invasion and metastasis of certain malignant cell types.
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PMID:Laminin and fibronectin promote the haptotactic migration of B16 mouse melanoma cells in vitro. 671 9

The role of glycoconjugates in cell surface and blood-borne implantation properties of murine metastatic melanoma sublines of low (B16-F1) or high (B16-F10) potential to colonize lungs was investigated by treating melanoma cells with the antibiotic tunicamycin. This drug prevents glycosylation of glycoproteins by inhibiting the formation of lipid-linked oligosaccharide precursors. The degree of tunicamycin-mediated modifications in glycoproteins was assessed by monitoring the decrease in cell surface sialogalactoproteins by binding of 125I-labeled Ricinus communis agglutinin I. Scanning electron microscopy of tunicamycin-treated B16-F1 and B16-F10 cells showed morphologic changes such as cell rounding and formation of numerous surface blebs. Tunicamycin-treated B16-F1 and B16-F10 cells lost their lung colonization abilities when injected intravenously into C57BL/6 mice, concomitant with lowered rates of adhesion to endothelial cell monolayers, endothelial extracellular matrix (basal lamina), and polyvinyl-immobilized fibronectin in vitro, suggesting that this drug inhibits experimental metastasis by modifying the surface glycoproteins involved in determining the adhesive properties of malignant cells.
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PMID:The role of glycoconjugates in metastatic melanoma blood-borne arrest and cell surface properties. 732 76

Disintegrins are Arg-Gly-Asp-containing proteins that inhibit integrin-mediated cell-cell and cell-matrix interactions. We have purified a disintegrin, contortrostatin, from Agkistrodon contortrix contortrix snake venom that is a potent inhibitor of human metastatic melanoma (M24 met) cell adhesion to extracellular matrix proteins. Contortrostatin inhibits M24 met cell adhesion to type I collagen, vitronectin, and fibronectin with 50% inhibitory concentration values of 20, 75, and 220 nM, respectively. Contortrostatin does not significantly inhibit adhesion of M24 met cells to laminin. 125I-labeled contortrostatin binds to M24 met cells in a saturable and displaceable manner. Scatchard analysis indicates that there are two binding sites for 125I-labeled contortrostatin on the surface of these cells. High affinity binding has a Kd of 3 nM with 165,000 sites/cells low affinity binding has a Kd of 60 nM with 500,000 sites/cell. Immobilized contortrostatin can support adhesion of M24 met cells; this binding is blocked by a monoclonal antibody to the beta 1 integrin subunit and by an antibody to the fibronectin receptor alpha 5 beta 1. The anti-vitronectin receptor (alpha v beta 5) monoclonal antibody which blocks adhesion of M24 met cells to immobilized vitronectin does not block binding of M24 met cells to immobilized contortrostatin. In an in vivo experimental metastasis model system, contortrostatin at 20 micrograms and 100 micrograms inhibits lung colonization of M24 met cells (5 x 10(5)), injected in the tail vein of scid mice, by 51 and 73%, respectively. We conclude that contortrostatin is a potent inhibitor of beta 1 integrin-mediated M24 met cell adhesion in vitro and that it also inhibits lung colonization in vivo.
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PMID:Contortrostatin, a snake venom disintegrin, inhibits beta 1 integrin-mediated human metastatic melanoma cell adhesion and blocks experimental metastasis. 752 Aug 32

The carbohydrate structures of the beta 1 integrins obtained from a mouse metastatic melanoma B16 F1 and its weakly metastatic wheat-germ agglutinin-resistant mutant Wa4-b1 were studied comparatively. The results indicated that the integrins from both cells contain high mannose-type and bi-, tri- and tetra-antennary complex-type sugar chains. No significant difference was found in the outer chain branching between both integrins, but sialylation of the sugar chains of the mutant's integrin was markedly decreased and almost all the outer chain moieties of tri- and tetra-antennary oligosaccharides of the mutant's integrin were fucosylated, resulting in the formation of X-antigenic determinants, Gal beta 1-->4 (Fuc alpha 1-->3) GlcNAc. In contrast, the integrin from parental cell contained no X-antigenic determinant. These structural differences found in the integrin are thought to account for the reduction in the metastatic potential of the mutant which also shows reduced adhesion to fibronectin and laminin as compared with the parental cell.
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PMID:Altered glycosylation of beta 1 integrins associated with reduced adhesiveness to fibronectin and laminin. 767 33

We have recently reported that concomitant with an increase in invasiveness, there is an increase in the expression and secretion of the matrix-degrading 72 kDa gelatinase A/type IV collagenase (MMP-2) in a moderately invasive human melanoma cell line (A375M) upon perturbation of the alpha v beta 3 classic vitronectin receptor. In the present study, we have extended these observations to include a highly invasive and metastatic melanoma cell line (C8161) which expresses a comparable amount of the alpha 5 beta 1 integrin (classic fibronectin receptor), but very little alpha v beta 3 integrin on its surface. When perturbed with an anti-alpha 5 beta 1 antibody, C8161 cells are 89% more invasive in vitro, and express and secrete increased levels of the gelatinase A. These changes were not elicited using antibodies to the alpha v beta 3 integrin. In addition, a 73% increase in invasion of C8161 cells through a fibronectin-enhanced matrix occurred, which could be abrogated by neutralizing antibodies to gelatinase A. Furthermore, we attempted to transiently mimic the invasive phenotype of the C8161 cells by diminishing the alpha v beta 3 integrin from the A375M cell surface through fluorescence-activated cell sorting selection or deoxynojirimycin treatment, and found these cells to be 30-50% more invasive than the parental population. These data suggest that alternative modulation and signaling events could be involved in melanoma tumor cell invasion as a result of the differential expression of integrins, and strictly cataloging the presence of these integrins is but an initial step in the analysis of their functional activity.
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PMID:The 72 kDa type IV collagenase is modulated via differential expression of alpha v beta 3 and alpha 5 beta 1 integrins during human melanoma cell invasion. 768 18


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