Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of reports linking mutant p53 (mp53) to decreased expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) and increased angiogenesis, we compared primary and metastatic melanoma tumor specimens to determine if these factors were associated with metastatic progression. Western blotting, immunohistochemistry (IHC), and image analysis (IA) techniques were employed to evaluate the relationship between p53 status and TSP-1 expression in Zaz and M14 melanoma cell lines, and among p53, TSP-1, and angiogenesis in primary and metastatic melanomas. Zaz cells expressed wild-type p53 (WT p53) and high levels of TSP-1, while the M14 cells expressed mp53 and low TSP-1 levels. Examination of clinical melanoma specimens (N = 99) revealed an incidence of mp53 of 48%. Specimens with WT p53 (N = 46) expressed significantly higher mean levels of TSP-1 (41 +/- 27 vs. 21 +/- 24; p = 0.0004), and lower microvessel counts per 200x field (25 +/- 17 vs. 40 +/- 20; p = 0.0001) than tumors expressing mp53 (N = 42). A significantly higher incidence of mp53 expression was seen in metastatic tumors (64%, 37/58) than in primary tumors (27%, 11/41)(p < 0.0005). Primary tumors specimens had higher levels of TSP-1 (40 +/- 27 vs. 25 +/- 25; p = 0.0054) and lower microvessel counts (26 +/- 18 vs. 39 +/- 20, p = 0.0013) than metastatic tumors. These data suggest that acquisition of mp53, decreased TSP-1, and increased microvessel infiltration may be interrelated and associated with the metastatic phenotype in malignant melanoma.
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PMID:Mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma. 961 39

Neovascularisation is a key step in tumour growth and establishment of distant metastases. We have recently demonstrated that the thienopyridine SR 25989 an enantiomer of the anti-aggregant clopidogrel (Plavix) lacking anti-aggregant activity, inhibits endothelial cell proliferation in vitro by increasing the expression of endogenous thrombospondin-1, a natural potent inhibitor of angiogenesis. The anti-angiogenic effect of SR 25989 was further assessed in vitro in a quantitative assay of angiogenesis comprising a fragment of rat aorta embedded in a fibrin gel and in vivo in a pulmonary metastatic model using C57BL/6 mice inoculated in the foot pad with the highly metastatic melanoma cell line B16 F10. SR 25989 induced a dose dependent inhibition of spontaneous microvessel development in vitro reaching half maximal inhibition at around less than 50 microM and caused platelet derived growth factor induced angiogenesis to regress as a function of thienopyridine concentration. In vivo, SR 25989 did not alter significantly the growth rate of the primary tumour in the foot pad and did not inhibit development of inguinal nodes which appeared after amputation. However, the number and size of lung metastases were reduced in treated animals when examined at the time of sacrifice. In addition, the few metastases over 1 mm3 did not show any neovascularisation, as confirmed by negative von Willebrand immunostaining and in contrast to intense vascularisation seen in metastases developed by control mice. These results confirm that SR 25989 possesses potent anti-angiogenic properties and is able to inhibit metastatic dissemination and growth. The lack of effect on the primary tumour and inguinal nodes illustrates the complexity of the mechanisms involved in tumoural neo-angiogenesis and points out the possibility for distinct processes leading to neovascularisation in primary tumour as opposed to metastases.
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PMID:Anti-angiogenic effects of the thienopyridine SR 25989 in vitro and in vivo in a murine pulmonary metastasis model. 1187 46

Protein-protein interactions are governed by a variety of structural features. The sequence specificities of such interactions are usually easier to establish than the "topological specificities," whereby interactions may be classified based on recognition of distinct three-dimensional structural motifs. Approaches to explore topological specificities have been based primarily on assembly of mini-proteins with well defined secondary, tertiary, and/or quarternary structures. The present chapter focuses on three approaches for constructing topologically well defined mini-proteins: template-assembled synthetic proteins (TASPs), disulfide-stabilized structures, and peptide-amphiphiles (PAs). Specific examples are given for applying each approach to explore topologically-dependent protein-protein interactions. TASPs are utilized to identify a metastatic melanoma receptor that binds to the alpha1(IV)1263-1277 region of basement membrane (type IV) collagen. A disulfide-stabilized structure incorporating a sarafotoxin (SRT) 6b model was examined as a matrix metalloproteinase (MMP)-3 inhibitor. PAs were developed as (a) fluorogenic triple-helical or polyPro II substrates for MMPs and aggrecanase members of the a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family and (b) glycosylated and nonglycosylated ligands for metastatic melanoma cells. Topologically constrained mini-proteins have proved to be quite versatile, helping to define critical primary, secondary, and tertiary structural elements that modulate enzyme and receptor functions.
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PMID:Application of topologically constrained mini-proteins as ligands, substrates, and inhibitors. 1860 45

The proteolytic activities of a disintegrin and metalloproteinase (ADAM); a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and matrix metalloproteinase (MMP) families play important roles in normal and multiple pathological conditions. These metalloproteases have potential roles in the degradation of the ECM and in the processing of bioactive molecules. In the present study, RNA was isolated from multiple normal fibroblast and metastatic melanoma cell lines, as well as the isogenic normal tissue and tumor samples, and the gene expression levels of six ADAMs, eight MMPs, and four ADAMTSs were analyzed by real-time PCR. This approach allowed for detected changes in mRNA expression of the individual metalloproteinase genes to be compared between normal and metastatic states and also between tissue and cultured cells. Increased gene expression of several ADAM and MMP family members (MMP1, MMP8, MMP15, and ADAM15) occurred in melanoma tissue and was replicated in tissue cultures. In general, the level of ADAM and MMP mRNA expression was several-fold higher in cultured cells compared with the isogenic tissue from which they were derived. Passage-dependent expression patterns were observed for MMP8 and MMP9 in in-house-derived metastatic melanoma cell lines. This reiterates earlier suggestions that experiments using cells that have been maintained in culture should be interpreted with great care.
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PMID:Variability in melanoma metalloproteinase expression profiling. 2111 30

Human adipose tissue derived mesenchymal stem cells (hAD-MSCS) with suppressive immunogenicity, homing to injury, inflammatory, and cancer sites can be suitable for gene therapy. PiggyBac (PB) is a type of transposon vector applied in mammalian systems and could overcome some limitations of other transposon and viral vectors. In this study, the therapeutic potential hAD-MSCs expressing thrombospondin-1 (TSP-1) is assessed through tail vein injection in C57BL/6 models bearing melanoma mice. Twenty days after injection, antiangiogenic effects and number of activated T. cells are assessed by Immunohistochemistry (IHC) method. Apoptosis value is analyzed by tunnel assay. Mice survival and numbers of nodules in mice lungs also are assessed. By western blotting, value of TSP-1, Bax and Bcl2 expression are assessed. The result revealed that hAD-MSCs.TSP-1 can inhibit angiogenesis and induce apoptosis and activated T. cells in a significant manner in C57BL/6 mice models bearing melanoma. Survival also significantly increased and number of nodules decreased, value of Bax and TSP-1 expression increased and value of Bcl2 expression decreased. In conclusion, our result showed that hAD-MSC. TSP-1 can be applied as an effective delivery vehicle in lung metastatic melanoma therapy.
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PMID:Novel application of adipose-derived mesenchymal stem cells via producing antiangiogenic factor TSP-1 in lung metastatic melanoma animal model. 3303 82