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

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

We previously demonstrated that expression of the cell surface adhesion molecule MCAM/MUC18 correlates directly with the metastatic potential of human melanoma cells. In addition, the progression of human melanoma towards the metastatic phenotype is associated with loss of expression of the tyrosine-kinase receptor c-KIT. This review summarizes our recent data demonstrating that the expression of both genes is regulated by the AP-2 transcription factor. Moreover, we have observed a loss of AP-2 expression in metastatic melanoma cells. Re-expression of AP-2 in the highly metastatic A375SM cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice. MCAM/MUC18 mRNA and protein expression was significantly downregulated while c-KIT expression was upregulated in the AP-2 transfected cells. Since AP-2 also regulates other genes that are involved in the progression of human melanoma such as E-cadherin, MMP-2, p21WAF-1, HER-2, BCL-2, and insulin like growth factor receptor-1, we propose that loss of AP-2 is a crucial event in the development of malignant melanoma.
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PMID:Role of AP-2 in tumor growth and metastasis of human melanoma. 1072 91

The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase [(VGP), metastatic phenotype] are not very well defined. We previously demonstrated that expression of the cell-surface adhesion molecule MCAM/MUC18 correlates directly with the metastatic potential of human melanoma cells. In addition, the progression of human melanoma towards the metastatic phenotype is associated with loss of expression of the tyrosine-kinase receptor c-KIT. In this review, I will summarize our recent studies demonstrating that the expression of both genes is regulated by the AP-2 transcription factor. Moreover, we have observed a loss of AP-2 expression in metastatic melanoma cells. Re-expression of AP-2 in the highly metastatic A375SM cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice. MCAM/MUC18 mRNA and protein expression was significantly down-regulated while c-KIT expression was up-regulated in the AP-2-transfected cells. To further investigate the role of AP-2 in the progression of human melanoma, we attempted to inactivate AP-2 in primary cutaneous melanoma by using a dominant-negative AP-2, or the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice, and upregulated MMP-2 expression and activity. As AP-2 also regulates other genes that are involved in the progression of human melanoma such as E-cadherin, p21/WAF-1, HER2/neu, Bcl-2, FAS/APO-1, IGF-R-1, VEGF and the thrombin receptor (PAR-1), we therefore propose that loss of AP-2 is a crucial event in the development of malignant melanoma. In addition, the transition of melanoma cells from RGP to VGP is also associated with over-expression of the transcription factors CREB and ATF-1. The notion that the balance between AP-2 and CREB/ATF-1 expression determines the progression of melanoma cells towards the metastatic phenotype will be discussed.
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PMID:Gene regulation in melanoma progression by the AP-2 transcription factor. 1131 Jul 95

Expression of MMP-2 in melanoma cells has been demonstrated to be involved in the degradation of extracellular matrix during melanoma growth and to correlate with later melanoma metastasis. MMP-2 is considered to be activated by membrane-associated matrix metalloproteinases (MT-MMPs). To know whether MT-MMPs are involved in the activation of MMP-2 in melanoma cells, immunohistochemical studies were performed in primary and metastatic melanoma by use of the antibodies for MT1-MMP, MT2-MMP and MT3-MMP. Expression of MT1-MMP, MT2-MMP, MT3-MMP and MMP-2 in nevocellular nevus (n = 5), dysplastic nevus (n = 2) and juvenile melanoma (n = 3) was undetectable or detected in only a few cells. Superficial spreading melanoma (SSM) (n = 3) and acral lentiginous melanoma (ALM) (n = 3) showed a moderate expression of MT1 approximately 3-MMP. In nodular melanoma (NM) (n = 2) and metastatic melanoma (n = 3), MT1 approximately 3-MMP was more intensely expressed. Double immunofluorescence demonstrated a consistent colocalization of MT2-MMP/MMP-2 and MT3-MMP/MMP-2 in the NM and metastatic melanoma cells. The colocalization of MT2,3-MMP and MMP-2 in nodular and metastatic melanoma cells suggests that MT-MMPs and MMP-2 co-operate in the invasive and metastatic process of melanoma cells.
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PMID:Coordinate expression of membrane type-matrix metalloproteinases-2 and 3 (MT2-MMP and MT3-MMP) and matrix metalloproteinase-2 (MMP-2) in primary and metastatic melanoma cells. 1152 48

Activating transcription factor-1 (ATF-1) and cAMP-responsive element (CRE)-binding protein (CREB) have been implicated in cAMP and Ca2+-induced transcriptional activation. The expression of the transcription factors ATF-1 and CREB is upregulated in metastatic melanoma cells. However, how overexpression of ATF-1/CREB contributes to the acquisition of the metastatic phenotype is unclear. Previously we demonstrated that quenching of CREB activity in metastatic melanoma cells by means of a dominant-negative form of CREB (KCREB) led to a decrease in their tumorigenicity and metastatic potential in nude mice. We identified two mechanisms that explain how overexpression of CREB/ATF-1 contributes to the metastatic phenotype. The first is one in which CREB/ATF-1 play an essential role in invasion by regulating the CRE-dependent expression of the metalloproteinase MMP-2 and the adhesion molecule MCAM/MUC18 genes. In the second mechanism, CREB and ATF-1 act as survival factors for human melanoma cells. Here, the effect of disrupting ATF-1 activity was investigated using intracellular expression of an inhibitory anti-ATF-1 single chain antibody fragment (ScFv). Intracellular expression of ScFv anti-ATF-1 in MeWo melanoma cells caused significant reduction in CRE-dependent promoter activation. In addition, expression of ScFv anti-ATF-1 in melanoma cells suppressed their tumorigenicity and metastatic potential in nude mice. ScFv anti-ATF-1 rendered the melanoma cells susceptible to thapsigargin-induced apoptosis in vitro and caused massive apoptosis in tumors transplanted subcutaneously into nude mice, confirming that AFT-1/CREB act as survival factors for human melanoma cells. These studies demonstrate the potential usage of ScFv anti-ATF-1 as an inhibitor of tumor growth and metastasis of solid tumors in vivo.
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PMID:Targeting the ATF-1/CREB transcription factors by single chain Fv fragment in human melanoma: potential modality for cancer therapy. 1164 9

The laminin 5 (Ln-5) gamma2 chain and matrix metalloproteinases (MMPs) MMP-2 and membrane type 1 (MT1)-MMP act cooperatively and are required for highly aggressive melanoma cells to engage in vasculogenic mimicry when cultured on a three-dimensional matrix. Furthermore, generation of Ln-5 gamma2 chain promigratory fragments by MMP-2 and MT1-MMP proteolysis is necessary for an aggressive tumor cell-preconditioned matrix to induce vasculogenic mimicry in poorly aggressive tumor cells. These observations suggest that treatment regimes that specifically target aggressive tumor cells may fail to take into account changes in the extracellular microenvironment that persist after removal or destruction of an aggressive tumor and could result in a recurrence or continuance of the tumor. As a potential therapeutic approach to address this concern, the work presented here measured the molecular consequences of adding a chemically modified tetracycline (CMT-3; COL-3) that inhibits MMP activity to aggressive metastatic melanoma cells in three-dimensional culture. COL-3 inhibited vasculogenic mimicry and the expression of vasculogenic mimicry-associated genes in aggressive cells, as well as the induction of vasculogenic mimicry in poorly aggressive cells seeded onto an aggressive cell-preconditioned matrix. Furthermore, molecular analysis revealed that COL-3 not only inhibited the generation of Ln-5 gamma2 chain promigratory fragments in the aggressive cell-preconditioned matrix but also inhibited the induction of Ln-5 gamma2 chain gene expression in poorly aggressive cells by the aggressive cell-preconditioned matrix. These results suggest that COL-3 (and related chemically modified tetracyclines) may be useful in targeting molecular cues in the microenvironment of aggressive tumors and could potentially be used in a combinatorial manner with other therapies that specifically target and kill aggressive tumor cells.
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PMID:Targeting the tumor microenvironment with chemically modified tetracyclines: inhibition of laminin 5 gamma2 chain promigratory fragments and vasculogenic mimicry. 1247 98

Melanoma begins with benign nevi and progresses to radial growth phase (RGP) and to vertical growth phase [(VGP), metastatic phenotype]. The molecular changes associated with these transitions are not yet well defined. However, transcriptional regulation of some genes that are critical in melanoma progression is beginning to be elucidated. The first part of this review will focus on our recent studies demonstrating that progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18 and MMP-2, and lack of expression of c-KIT. In further investigations, we inactivated AP-2 in SB-2 primary cutaneous melanoma cells by using a dominant-negative AP-2, the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice and upregulated MMP-2 expression and activity. We have also recently demonstrated that loss of AP-2 expression in metastatic melanoma cells resulted in overproduction of the thrombin receptor, PAR-1. Other studies have shown that AP-2 regulates additional genes involved in melanoma development and progression, including E-cadherin, p21/WAF-1, HER2, Bcl-2, FAS/APO-1, IGF-R-1, and VEGF. We propose that loss of AP-2 is crucial in the development of malignant melanoma. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of two transcription factors, CREB and ATF-1, both of which may act as survival factors for human melanoma cells. The second part of the review will briefly discuss the role of other transcription factors, including ATF-2, SNAIL, MITF, and NFkappaB in the progression of human melanoma and will summarize recent knowledge on how changes in the expression of these transcription factors contribute to acquisition of the metastatic phenotype in human melanoma.
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PMID:Transcriptional regulation of metastasis-related genes in human melanoma. 1274 83

To determine treatment strategies and predict the clinical outcome of patients with melanoma it is important to understand the etiology of this disease. Recently, there has been some insight into molecular basis of melanoma including identification of a few of the regulatory factors and genes involved in this disease. For instance, the transcription factor AP-2 plays a tumor suppressor-like role in melanoma progression by regulating genes involved in tumor growth and metastasis. Previously, we have shown that the progression of human melanoma to the metastatic phenotype is associated with loss of AP-2 expression and deregulation of target genes such as MUC18/MCAM, c-KIT, and MMP-2. Increasing evidence demonstrates that the thrombin receptor (protease-activated receptor-1, PAR-1) plays a major role in tumor invasion and contributes to the metastatic phenotype of human melanoma. This review focuses on the role of the thrombin receptor in melanoma and its regulation by AP-2. We show that loss of AP-2 expression in metastatic melanoma cells correlates with overexpression of the thrombin receptor. Our analysis of AP-2/Sp1 complexes within the regulatory region of the thrombin receptor demonstrates that AP-2 binds the proximal 3' region of the promoter and diminishes PAR-1 expression. Levels of AP-2 and Sp1 proteins in a panel of melanoma cell lines demonstrated a marked decrease in the ratio of AP-2/Sp1, a decrease that correlated with overexpression of PAR-1 in metastatic melanoma cells. We propose that loss of AP-2 results in increased expression of the thrombin receptor, which subsequently contributes to the metastatic phenotype of melanoma by upregulating the expression of adhesion molecules, proteases, and angiogenic molecules.
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PMID:Role and regulation of the thrombin receptor (PAR-1) in human melanoma. 1278 89

The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP, metastatic phenotype) are not yet well defined. We have demonstrated that the progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18, MMP-2, the thrombin receptor (PAR-1), and lack of c-KIT expression. The transition from RGP to VGP is also associated with overexpression of the angiogenic factor IL-8. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of the transcription factors CREB and ATF-1, both of which may act as survival factors for human melanoma cells. Inactivation of CREB/ATF-1 activities in metastatic melanoma cells by dominant-negative CREB or by anti-ATF-1 single chain antibody fragment (ScFv), resulted in deregulation of MMP-2 and MCAM/MUC18, increased the sensitivity of melanoma cells to apoptosis, and inhibition of their tumorigenicity and metastatic potential in vivo. In this prospect article, we summarize our data on the role of AP-2 and CREB/ATF-1 in the progression of human melanoma and report on the development of new fully human antibodies anti-MCAM/MUC18 and anti-IL-8 which could serve as new modalities for the treatment of melanoma.
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PMID:Regulation of gene expression in melanoma: new approaches for treatment. 1552 74

Overexpression of cAMP-response element (CRE)-binding protein (CREB) and activating transcription factor (ATF) 1 contributes to melanoma progression and metastasis at least in part by promoting tumor cell survival and stimulating matrix metalloproteinase (MMP) 2 expression. However, little is known about the regulation of CREB and ATF-1 activities and their phosphorylation within the tumor microenvironment. We analyzed the effect of platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, for its ability to activate CREB and ATF-1 in eight cultured human melanoma cell lines, and we found that PAF receptor (PAFR) was expressed in all eight lines. In metastatic melanoma cell lines, PAF induced CREB and ATF-1 phosphorylation via a PAFR-mediated signal transduction mechanism that required pertussis toxin-insensitive Galphaq protein and adenylate cyclase activity and was antagonized by a cAMP-dependent protein kinase A and p38 MAPK inhibitors. Addition of PAF to metastatic A375SM cells stimulated CRE-dependent transcription, as observed in a luciferase reporter assay, without increasing the CRE DNA binding capacity of CREB. Furthermore, PAF stimulated the gelatinase activity of MMP-2 by activating transcription and MMP-2 expression. MMP-2 activation correlated with the PAF-induced increase in the expression of an MMP-2 activator, membrane type 1 MMP. PAF-induced expression of pro-MMP-2 was causally related to PAF-induced CREB and ATF-1 phosphorylation; it was prevented by PAFR antagonist and inhibitors of p38 MAPK and protein kinase A and was abrogated upon quenching of CREB and ATF-1 activities by forced overexpression of a dominant-negative form of CREB. PAF-induced MMP-2 activation was also down-regulated by p38 MAPK and protein kinase A inhibitors. Finally, PAFR antagonist PCA4248 inhibited the development of A375SM lung metastasis in nude mice. This result indicated that PAF acts as a promoter of melanoma metastasis in vivo. We proposed that metastatic melanoma cells overexpressing CREB/ATF-1 are better equipped than nonmetastatic cells to respond to PAF within the tumor microenvironment.
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PMID:Platelet-activating factor mediates MMP-2 expression and activation via phosphorylation of cAMP-response element-binding protein and contributes to melanoma metastasis. 1630 50


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