UMLS:C0278883 - FACTA Search

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

Interleukin 15 (IL-15) is a novel cytokine that shares no homology with IL-2, but it requires the use of beta and gamma chains of the IL-2 receptor complex for binding and signaling. In vitro studies have shown induction of CTL and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMCs) from normal donors by IL-15 against known tumor targets. The present study attempts to define the role of IL-15 in generating LAK activity from melanoma patient lymphocytes. PBMCs of patients newly diagnosed with metastatic melanoma were incubated with different doses of recombinant human IL-15 and tested against autologous tumor cells, LAK sensitive cell lines (i.e., FMEX and Daudi), as well as the natural killer-sensitive cell line K562, in a 15-h 51Cr release assay. The effect of IL-15 was found to be both time and dose dependent, with peak activity detected after 2 or 3 days of culture with 100 ng/ml of this cytokine. LAK and not CTL activity in patient PBMCs was detected by the inability of mAbs against CD4, CD8, and MHC class I to effectively block lysis of autologous tumor and FMEX melanoma cells. In addition, interaction via the CD18 adhesion molecule was shown to be critical in IL-15-induced LAK-mediated lysis of autologous tumor cells. Finally, incubation of patient PBMCs with IL-15 for 6 h resulted in the up-regulation of perforin mRNA transcription. These findings suggest that LAK activity can be generated from melanoma patient PBMCs in the presence of IL-15 to lyse autologous tumor cells in a non-MHC-restricted manner. This new cytokine may play an important role in antitumor immunity with a possible use for cancer immunotherapy.
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PMID:Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism. 758 40

Homeobox-containing genes comprise a gene family coding for transcription factors involved in normal development. Class I human homeobox (HOX) genes display a peculiar chromosomal organization, perhaps directly related to their function. Aberrant expression of homeobox genes has been associated with both morphological abnormalities and oncogenesis. We have reported that HOX gene expression is (i) specific for normal adult human organs (kidney, colon, lung) and (ii) altered in cancer specimens according to their histological type and stage of tumor progression. Here, we have investigated whether patterns of HOX gene expression are associated with tumor heterogeneity by analyzing the expression of the entire panel of 38 HOX genes in clones isolated from a single human metastatic melanoma call line (Me 665/2). The differential expression of a block of genes located at the 5' end of the HOX C locus allows melanoma clones to be classified into 2 major groups. The 2 patterns of HOX gene expression are inversely associated with 2 distinct surface phenotypes for integrins (VLA-2, VLA-5 and VLA-6) and the adhesion molecule ICAM-1. The genes of the HOX C locus are silent in the clones with high levels of integrins VLA-2, VLA-5 and VLA-6 and of the adhesion molecule ICAM-1 but actively expressed in the clones with low levels of ICAM-1 and lacking VLA-2, VLA-5 and VLA-6. Our results indicate that HOX gene expression reflects the intra-tumor heterogeneity of melanoma clones and suggest that the expression of surface molecules involved in cell-cell and cell-matrix interactions may be related to the patterns of HOX gene expression.
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PMID:Differential patterns of HOX gene expression are associated with specific integrin and ICAM profiles in clonal populations isolated from a single human melanoma metastasis. 864 34

It has been recently suggested that soluble tumour necrosis factor receptors (sTNF-Rs) may represent prognostic factors in cancer. In malignant melanoma, the intercellular adhesion molecule (ICAM-1) has been described as involved in progression of the disease and is upregulated by TNF alpha. We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (sICAM-1). Significantly raised sTNF-R1 levels were detected only in patients with metastatic melanoma compared with normal controls (P < 0.002), whereas sTNF-R2 levels were increased both in primary and metastatic melanoma (P < 0.001). The ratio of type 2 to type 1 proteins increased in malignant melanoma compared with the controls but remained constant with the progression of the disease. A correlation between sTNF-Rs and sICAM-1 concentrations in patients' sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumour progression.
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PMID:Tumour necrosis factor (TNF) soluble receptors in malignant melanoma: correlation with soluble ICAM-1 levels. 881 90

Lung-endothelial cell adhesion molecule-1 (Lu-ECAM-1) is an endothelial cell surface molecule that mediates adhesion of metastatic melanoma cells to lung endothelium. Here we analyze the organization of the Lu-ECAM-1 protein complex, report the sequence of Lu-ECAM-1 cDNAs, and reveal a novel function of the protein. Lu-ECAM-1 immunopurified from bovine aortic endothelial cells (BAEC) consists of tightly associated glycoproteins of 90, 38, and 32 kDa, with minor components of 130 and 120 kDa. We present evidence that all of these protein species are encoded by a single open reading frame whose initial translation product is proteolytically processed to yield the other products. Correct processing in vitro was demonstrated by transfection of the longest cDNA into human embryonic kidney 293 cells; immunoblot analysis showed that the approximately 120-kDa precursor gave rise to 90- and 38-kDa products. RNA blots of BAEC mRNA detected messages in agreement with the sizes of the cDNA clones in addition to several of high molecular weight. DNA blot analysis showed that Lu-ECAM-1 is conserved throughout its length in all mammals tested, usually as a single or low copy gene. In the bovine, Lu-ECAM-1 protein is 88% identical to a calcium-dependent chloride channel described recently in tracheal epithelium, Ca-CC. Probes for Lu-ECAM-1 mRNA and protein confirmed the presence of a homolog in this tissue. We show that messages for both proteins are present in lung while only Ca-CC is present in trachea and only Lu-ECAM-1 is present in BAEC. These results suggest that endothelial cells express a chloride channel that is related to, but distinct from, that expressed in tracheal epithelium. They further suggest that an adhesion molecule can also be a chloride channel.
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PMID:Cloning and characterization of lung-endothelial cell adhesion molecule-1 suggest it is an endothelial chloride channel. 934 32

Tumour angiogenesis is essential for tumour growth and metastasis. Several lines of evidence indicate that vascular endothelial growth factor (VEGF) is a major regulator both of physiological and pathological angiogenesis. In this study we assessed the blood vessel density and VEGF expression of 94 melanoma metastases of 70 patients by immunohistochemistry, utilizing antibodies against human platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) and VEGF. The number of blood vessels ranged from 4 to 131 vessels/high power field (HPF), with a mean value of 32 vessels/HPF (+/-21) and a median of 29 vessels/ HPF. Survival since diagnosis of the primary disease and from the start of chemoimmunotherapy, as well as the disease-free survival period, was significantly shorter in the high vascularity group of patients compared with the low vascularity group (P< 0.05 and P< 0.01, respectively). A high overall expression of VEGF in the metastatic melanoma samples was observed. The degree of VEGF expression appeared to have a strong association with the blood vessel density (P= 0.017). This study demonstrates the clinical role of tumour vascularity in the prognosis of patients with metastatic melanoma. In addition, the strong association between vascularity and VEGF expression suggests a crucial role for this growth factor in the neovascularization of metastatic melanoma.
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PMID:Prognostic value of tumour vascularity in metastatic melanoma and association of blood vessel density with vascular endothelial growth factor expression. 1033 35

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 cell surface adhesion molecule human MUC18 (huMUC18 or Mel-CAM) has been postulated to play a key pathogenic role in metastatic melanoma progression. To establish an immunocompetent syngeneic mouse model that would greatly facilitate our understanding of the role of MUC18 in the metastatic behavior of melanoma, we cloned and characterized the mouse MUC18 (muMUC18) cDNA gene. The gene was amplified by RT-PCR and RACE of the poly(A)+RNA isolated from the mouse melanoma cell line B16F10/Queens. The cloned muMUC18 cDNA gene contained 28 nucleotides of 5'-UTR, 908 nucleotides of 3'-UTR, and an open reading frame (ORF) of 1947 nucleotides encoding a protein of 648 amino acids, which is two amino acids longer than huMUC18. The size of the muMUC18 mRNA is about 3 kb with a shorter 3'-UTR than the huMUC18 mRNA (about 3.3 kb). Besides, the sequence in the 3' UTR of the two mRNAs is diverse with only 31% identity. The 5'-UTR and coding sequences of the muMUC18 cDNA are 72.4 and 80.6% identical to those of huMUC18, respectively. The deduced amino acid sequence of the muMUC18 cDNA is 76.2% identical to that of huMUC18. The amino acid sequences deduced from MUC18 cDNA sequences from six other mouse melanoma cell lines are identical except one to three residues, suggesting that the muMUC18 cDNA sequence determined in this report is correct. The muMUC18 protein is predicted to be slightly more acidic than the human protein. The levels of muMUC18 mRNA and protein in nine mouse melanoma cell lines were directly proportional to their ability to establish metastatic colonies in lungs of syngeneic mice. Most biological functions of the muMUC18 may be similar to the huMUC18.
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PMID:Isolation and characterization of mouse MUC18 cDNA gene, and correlation of MUC18 expression in mouse melanoma cell lines with metastatic ability. 1125 16

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

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 cell surface adhesion molecule Mel-CAM is highly expressed in advanced primary and metastatic melanoma. Mel-CAM was first described as an integral membrane glycoprotein of malignant melanoma cells. The murine monoclonal antibody MAd18-5D7 recognizes an epitope of the extracellular domain of Mel-CAM and is able to enhance Mel-CAM mediated adhesion of melanoma cells in aggregation assays. For the characterization of peptides that antigenically mimic surface-exposed areas of Mel-CAM we screened a newly constructed random pVIII-28aa bacteriophage peptide library against MAd18-5D7. After three panning rounds a population of phages binding to MAd18-5D7 was enriched. Peptides expressed on the surface of these phages were then tested for their specificity for the antibody's antigen binding site. DNA sequences coding for two specific peptide ligands were determined. One of the deduced amino acid sequences showed similarity to a portion of the sequence of the third immunoglobulin-like extracellular domain of Mel-CAM. Both peptides blocked the interaction of MAd18-5D7 with Mel-CAM present in a MelJuSo melanoma cell line lysate. Phage displayed as well as synthetic peptides inhibited in a dose-dependent manner the binding of MAd18-5D7 to recombinant Mel-CAM in enzyme-linked immunosorbent assay experiments. No such inhibition was observed using a panel of other anti-Mel-CAM antibodies. Our results clearly indicate that these 28mer peptides are structural equivalents of the MAd18-5D7 epitope of Mel-CAM and that they will be useful tools for further in vitro and in vivo studies of Mel-CAM mediated cell-cell interaction.
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PMID:Selection of mimotopes of the cell surface adhesion molecule Mel-CAM from a random pVIII-28aa phage peptide library. 1240 32

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