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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of beta 3 integrins is increased in invasive melanoma. In this study we show that K1735 cell proliferation is enhanced by the expression of either beta 3 or a constitutively active Src. We investigated possible modulators of FN matrix assembly and found that matrix metalloproteinase 2 (MMP2) was activated by alpha v beta 3. alpha v beta 3 integrin was localized to focal contacts whereas alpha v beta 5 was peripherally distributed. MMP2 was also activated by expression of CASrc. MMP2 activation inversely correlated with FN matrix assembly, in that it dramatically reduced the organization of a FN matrix. K1735 cell migration on VN and invasion through a reconstituted basement membrane were decreased in the presence of anti-MMP2 antibodies. These results demonstrate that the expression of the alpha v beta 3 complex modulates melanoma cell behavior including activation of Src, organization of the cytoskeleton, assembly of the extracellular matrix, cell motility, and activation of MMP2.
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PMID:Specific alpha v integrin receptors modulate K1735 murine melanoma cell behavior. 1292 91

The participation of BRCA1 (breast cancer 1) in DNA repair is well established, especially in mammary and ovarian cells. Our purpose was to develop a new in vivo radio-sensitizing therapy for melanoma. We therefore investigated the effect of downregulation of BRCA1 on irradiated melanoma cells using an anti-BRCA1 ribozyme. Our results show that BRCA1 downregulation increased radio-sensitivity of the A375 cell line, suggesting that BRCA1 could act as a caretaker in melanoma; however, as BRCA1 functions are not limited to maintaining genomic integrity but also regulate transcription and the cell cycle, we confirmed that the proliferative rate of BRCA1 downregulated clones did not change. We also demonstrate that: (1) among the major pro-angiogenic genes, FGF-2 was not increased before or after irradiation and vascular endothelial growth factor strongly inhibited after irradiation; (2) expression of two important metalloproteinases, matrix metalloproteinase 2 and 9, involved in melanoma metastasis were decreased before and after irradiation; (3) expression of their major inhibitor, tissue inhibitor of metalloproteinase, was mainly upregulated; and (4) that invasion of BRCA1 downregulated cells was modified. Together these data suggest that BRCA1 downregulation in melanoma cells did not make them more aggressive and could lead to new therapeutic strategies for this tumor, which is so difficult to control once metastasized.
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PMID:Downregulation of BRCA1 in A375 melanoma cell line increases radio-sensitivity and modifies metastatic and angiogenic gene expression. 1500 18

Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways inhibited the growth of TPras transgenic melanomas in severe combined immunodeficient mice, blocked invasive behavior, and reduced angiogenesis. The inhibitor Ly294002, which is specific for phosphatidylinositol 3'-kinase, effectively reduced melanoma cell growth both in vitro and in vivo. Both Ly294002 and U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, reduced invasion, which correlated with reduction of the metalloproteinase matrix metalloproteinase 2. Tumor angiogenesis was disrupted through inhibition of vascular endothelial growth factor production from the tumor cells and antiangiogenic effects on endothelial cells. Observations with TPras melanoma cells that express dominant negative Deltap85 or kinase-inactive Raf(301) supported the specificity of the phenomena observed with the chemical inhibitors. These studies demonstrate that topical treatment targeting Ras effectors is efficacious, without systemic toxicities, and may prove to be useful in treating and preventing the progression of cutaneous melanoma.
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PMID:Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice. 1505 11

Phellinus linteus (PL) is a fungus mainly found in tropical America, Africa and Asian countries including Korea, Japan and China. PL has been traditionally used for the treatment of arthritis, liver damage and cancer. However, little was known on the biological activity and characterization of Phellinus species in Cambodia. Thus, in the present study, the anti-metastatic mechanism of aqueous extract of Cambodian Phellinus linteus (CPL) was evaluated. Cambodian mushroom was identified as a Phellinus species with 99% homology of Phellinus linteus by DNA sequence analysis and comparison by the National Center for Biotechnology Information. CPL did not exhibit any significant cytotoxicity against B16BL6 cells, invasive melanoma cells at 1 mg/ml. However, CPL inhibited platelet aggregation induced by B16BL6 cells and also disrupted the adhesion to gelatin and invasion of B16BL6 cells in a concentration dependent manner. Similarly, CPL dose-dependently inhibited the pulmonary metastatic colonies in C57BL/6 mice intravenously injected by B16BL6 cells up to 55.5% at a dose of 50 mg/kg compared with untreated control. CPL also down-regulated the expression of urokinase type plasminogen activator (uPA), one of key proteins associated with invasion and metastasis of tumor cells in a concentration dependent fashion, while CPL didn't significantly affect the expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) by reverse transcriptase-polymerase chain reaction (RT-PCR). Taken together, these findings indicate that Cambodian Phellinus linteus may inhibit metastasis at least partly via regulation of uPA associated with tumor cell induced platelet aggregation (TCIPA) and also suggest a further study for isolation of active ingredients and the involvement of adhesion molecule signaling pathway.
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PMID:Cambodian Phellinus linteus inhibits experimental metastasis of melanoma cells in mice via regulation of urokinase type plasminogen activator. 1563 58

Several families of genes by and large located on the X chromosome encode proteins of unspecified function. Commonly known as cancer/testis (CT) antigens, they are considered, under normal conditions, only to be expressed in cells of the germ line and placenta. CT genes are also often expressed in cancer cells, hence their classification. Here we report that their expression in normal cells is wider spread and can be observed in cells with the potential for self-renewal and pleuripotency, namely, stem cells. Several CT genes and their products, CT antigens, including SSX, NY-ESO-1, and N-RAGE, were expressed in undifferentiated mesenchymal stem cells (MSCs) and down-regulated after osteocyte and adipocyte differentiation. To elucidate the possible overlapping function played by these genes in cancer and stem cells, a comparative analysis of the localization of their proteins was made. In addition, localization relative to other MSC markers was examined. This revealed that SSX localizes in the cytoplasm and overlap occurs in regions where matrix metalloproteinase 2 (MMP2) and vimentin accumulate. Nevertheless, it was found that no protein interactions between these molecules occur. Further investigation revealed that the migration of a melanoma cell line (DFW), which expresses SSX, MMP2, and vimentin, decreases when SSX is down-regulated. This decrease in cell migration was paralleled by a reduction in MMP2 levels. Analogous to this, SSX expression is down-regulated in MSCs after differentiation; concomitantly a reduction in MMP2 levels occurs. In addition, E-cadherin expression increases, mimicking a mesenchymal epithelial transition. These results afford SSX a functional role in normal stem cell migration and suggest a potentially similar function in cancer cell metastases.
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PMID:Cancer/testis antigen expression in human mesenchymal stem cells: down-regulation of SSX impairs cell migration and matrix metalloproteinase 2 expression. 1578 33

Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD) could function as a cell surface sensor for cell density, controlling the transition between local cell proliferation and tissue invasion in melanoma progression. We have tested the hypothesis that progressive cell clustering controls the proteolytic cascade for activation of gelatinase A/matrix metalloproteinase-2 (MMP-2), which involves formation of an intermediate ternary complex of membrane type 1 MMP (MT1-MMP/MMP-14), tissue inhibitor of metalloproteinase-2 (TIMP-2), and pro-MMP-2 at the cell surface. Surprisingly, truncation of ALCAM severely impaired MMP-2 activation in a nude mouse xenograft model, in which we previously observed diminished primary tumor growth and enhanced melanoma metastasis. Comparative studies of two-dimensional monolayer and three-dimensional collagen-gel cultures revealed that extensive cell-to-cell contacts, wild-type ALCAM, and cell-to-matrix interactions were all indispensable for efficient conversion of pro-MMP-2 to its active form in metastatic melanoma cells. Truncated, dominant-negative ALCAM diminished MMP-2 activation via reduced transcript levels and decreased processing of MT1-MMP. Failure of the proteolytic cascade after selective ALCAM depletion by RNA interference was mainly due to incomplete MT1-MMP processing, which was otherwise promoted by extensive cell-to-cell contacts. These data attribute a novel signaling role to ALCAM in regulation of proteolysis and support its previously postulated sensor function in invasive growth.
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PMID:Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a novel actor in invasive growth, controls matrix metalloproteinase activity. 1620 50

Degradation of elastin, the main amorphous component of elastic fibers, by elastases belonging to the serine, metallo, or cysteine families leads to the generation of elastin fragments, designated as elastokines in keeping with their cytokine-like properties. Generation of elastokines from one of the longest lived protein in human might represent a strong tissue repair signal. Indeed, they (1) exhibit potent chemotactic activity for leukocytes, (2) stimulate fibroblast and smooth muscle cell proliferation, and (3) display proangiogenic activity as potent as VEGF. However, continuous exposure of cells to these matrikines, through increased elastase(s) expression with age, can contribute to the formation of a chronic inflammatory state, that is, inflamm-aging. Importantly, binding of elastokines to S-Gal, their cognate receptor, proved to stimulate matrix metalloproteinase expression in normal and cancer cells. Besides, these elastin fragments can polarize lymphocytes toward a Th-1 response or induce an osteogenic response in smooth muscle cells, and arterial wall calcification. In this chapter, emphasis will be made on the contribution of elastokines on the genesis of age-related arterial wall diseases, particularly abdominal aortic aneurysms (AAAs). An elastokine theory of AAAs progression will be proposed. Age is one main risk factor of cancer incidence and development. The myriad of biological effects exerted by elastokines on stromal and inflammatory cells led us to hypothesize that they might be main actors in elaborating a favorable cancerization field in melanoma; for instance these peptides could catalyze the vertical growth phase transition in melanoma through increased expression of gelatinase A and membrane-type 1 matrix metalloproteinase.
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PMID:Elastin-elastases and inflamm-aging. 1749 49

Melanoma is a very aggressive and highly angiogenic tumor in which standard treatments have had only limited success. Patients with advanced disease have a 5-year survival rate of 5%. In search for alternatives, we identified a natural product extracted from the fungus Aspergillus niger, termed ACTIBIND, that inhibits tumor growth and metastasis of melanoma in vivo. ACTIBIND, a T2 RNase, exerts antitumorigenic and antiangiogenic activities by competing with the angiogenic factor angiogenin (itself an RNase homologue). Thus, there was decreased expression and activity of the matrix metalloproteinase 2 in melanoma and vascular endothelial cells, decreased vascularization, and increased tumor cell apoptosis in vivo. ACTIBIND significantly inhibited angiogenesis in an in vivo angiogenesis assay with sponges containing angiogenin. In vitro, ACTIBIND was internalized by both melanoma and human umbilical vein endothelial cells, reached the cell nuclei, and inhibited the activity of angiogenin response elements in a dose-dependent manner. Collectively, our data indicate that ACTIBIND should be tested for its potential as a new antiangiogenic modality for the treatment of melanoma.
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PMID:ACTIBIND, a T2 RNase, competes with angiogenin and inhibits human melanoma growth, angiogenesis, and metastasis. 1754 5

The aim of this study was to investigate whether tumor cells as well as tumor-associated macrophages (TAMs) contribute to the generation of protease activities essential to tumor cell invasiveness, such as matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9), and the urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR). We found that the enhanced invasiveness through Matrigel-coated filters of B16 murine melanoma cells stimulated with IFNgamma was associated with an higher expression of uPAR and MMP-9 in these cells. Moreover, treatment with anti-MMP-9 or anti-uPAR monoclonal antibodies abrogated the increase of invasiveness in IFNgamma-stimulated melanoma cells, suggesting a cooperation of uPA system and MMP-9 in cytokine-stimulated invasiveness. Invasiveness through Matrigel was also enhanced in B16 melanoma cells exposed to a medium conditioned by TAMs, represented in our experimental model by thioglycollate-elicited macrophages co-cultivated with melanoma cells. Macrophages isolated from these co-cultures were found to express higher levels of uPAR and MMP-9 compared to macrophage cultures alone, and the pro-invasive activity of the co-culture-conditioned medium was abrogated by anti-MMP-9 monoclonal antibodies, but not anti-uPAR monoclonal antibodies. Furthermore, the enhanced uPAR and MMP-9 expression in macrophages co-cultivated with tumor cells seems a rather specific phenomenon, generated through a cell-to-cell contact mechanism. On the whole, our data point to a cooperation between tumor cells and macrophages elicited by tumor cells themselves in generating key enzymes essential in the promotion of tumor invasiveness, such as uPAR and MMP-9.
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PMID:Tumoral and macrophage uPAR and MMP-9 contribute to the invasiveness of B16 murine melanoma cells. 1807 11

Collagen, the major constituent of human dermis, represents the main barrier against progression of melanoma cells. Several matrix metalloproteinases (MMPs), i.e. collagenase-1 (MMP-1), gelatinase A (MMP-2) and membrane-type 1-MMP (MMP-14), favor melanoma cell invasion through their capacity of degrading collagen and thus, are considered as main targets. Potent inhibitors, as hydroxamate-derived pseudopeptides were first proposed as pharmacological agents to control melanoma invasiveness. These molecules have major drawbacks linked to i) toxicity and ii) absence of specificity, in keeping with the high Zn chelating property of hydroxamates, that might hinder the contribution of the occupancy of other subsites in enzyme inhibition. To date, research focuses on the design of compounds which display a lower affinity for Zn in enzyme active site. For instance, hydroxamate can be replaced by phosphinic acid or hydrazide which further allows synthesis of both right- and left- hand side inhibitors and therefore occupancy of non-primed enzyme subsites. Novel types of selective MMP inhibitors also include non-competitive and mechanism-based inhibitors. Finally, collagenolysis may be controlled by modulating enzyme-substrate interaction through the identification of substances that bind to MMP exosites. Such compounds could be of value by impeding collagenases to associate to plasma-membrane of invading cancer cells.
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PMID:Control of melanoma invasiveness by anticollagenolytic agents: a reappraisal of an old concept. 1951 99


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