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

The role of growth factor networks in regulating the progression of human melanocytes towards tumorigenicity and ultimately the malignant phenotype is poorly understood. In particular, the autocrine and paracrine influences that modulate cellular invasion and extracellular matrix degradative enzymes of melanoma cells remain undefined at the molecular level. We report here that nerve growth factor (NGF) can modify some metastasis-associated cellular properties of human and mouse melanoma cells. Treatment of early-passage human metastatic melanoma cells (MeWo) or their variants (3S5, 70W) with biologically active 2.5S NGF resulted in (a) delayed density-dependent inhibition of melanoma cell growth; (b) increased in vitro invasion through a reconstituted basement membrane; and (c) time- and dose-dependent induction of heparanase, a heparan-sulfate-specific endo-beta-D-glucuronidase associated with human melanoma metastasis. These effects of NGF were most marked in the 70W brain-colonizing cells (70W > MeWo > 3S5). The NGF enhancement of heparanase secretion was not species-specific, since it was also observed in murine B16 melanoma cells; the highest NGF stimulation of heparanase was found in brain-colonizing murine B16-B15b variant (B16-B15b > B16-BL6, B16-F10, B16-F1). NGF also increased the invasive capacity of the human 70W and murine B16-B15b sublines in a chemoinvasion assay performed with filters coated with purified heparan sulfate proteoglycan (HSPG). The enhancement of chemotactic response and heparanase production was detected at NGF concentrations sufficient to fully saturate both low- and high-affinity NGF receptors (NGFR), the neurotrophin receptor (p75) and the trkA gene product, respectively. The results suggest that, in addition to the effects of NGF on cellular development and differentiation within the peripheral and central nervous systems, NGF can exert changes in the invasive properties of neuroectoderm-derived melanoma cells.
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PMID:Nerve growth factor effects on human and mouse melanoma cell invasion and heparanase production. 840 1

An important clinical endpoint in patients with cancer is formation of metastases in the brain. Understanding this phenomenon is important in several types of malignancies, including melanoma, lung and breast cancers. Metastatic tumor cells use specific adhesion molecules to home to brain, and there they must attach to microvessel endothelial cells and respond to brain endothelial cell-derived motility factors and brain invasion factors to invade the CNS. Neurotrophins are important invasion factors in this process, and the ability to invade into the brain may well depend on metastatic cell responses to neurotrophins and production of basement membrane-degradative enzymes capable of locally destroying the blood-brain barrier. Brain-metastatic human melanoma cells express low-affinity p75 receptor for neurotrophins such as nerve growth factor, but they do not express the high-affinity-type receptors for nerve growth factor encoded by the protooncogene trkA. Tumor cells can proliferate in the CNS in response to local paracrine growth factors and inhibitors, but their growth also depends on their producing and responding to autocrine growth factors. A major organ-derived (paracrine) growth factor has been isolated that differentially stimulates the growth of cells metastatic to the brain. Characterization of this mitogen demonstrated that it is a transferrin-like glycoprotein; cells that are metastatic to brain express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to other sites. Transferrin-like factors are expressed in fetal brain and could represent the transferrin-like factors that stimulate growth of brain-metastatic melanoma and breast cancer cells. These and other factors are probably important in determining whether metastatic cells can successfully invade, colonize, and grow in the CNS.
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PMID:Tumor metastasis to brain: role of endothelial cells, neurotrophins, and paracrine growth factors. 851 8

Chemotherapeutic agent-induced DNA cleavage gives rise to apoptosis in a subpopulation of SK-N-SH human neuroblastoma cells; the remaining cells undergo Schwann cell-like differentiation. Like other neural crest and primitive neurectodermal tumor-derived cell lines, SK-N-SH cultures contain cells of neural (N-type) and epithelial (substrate-adherent, or S-type) phenotypes. Using isolated N-type and S-type cells from neuroblastoma, medulloblastoma, melanoma and glioma cell lines, we demonstrate that the determinants of the response to DNA cleavage are intrinsic properties of the cell. Furthermore, using a series of analogues of enediyne deoxyribonucleic acid (DNA) cleaving agents, we show that the molecular target of these agents is likely to be the same in N- and S-type cells, implying that the difference in response characteristics is a function of different distal pathways that are triggered by DNA cleavage. We demonstrate that the concentration of the DNA damaging agent used, and not the specific characteristics of the damage it produces, is the trigger for production of the cellular response. Response type does not correlate with previously published values for expression of the apoptosis modulators Bcl-2, Bcl-XL, wildtype p53, or, in medulloblastoma lines, p75.
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PMID:Determinants of the response of neuroblastoma cells to DNA damage: the roles of pre-treatment cell morphology and chemical nature of the damage. 862 28

Melanoma is a malignant tumor with a varied histologic appearance. Melanoma composed of spindle cells may include desmoplastic and neurotropic melanoma. The histologic diagnosis of desmoplastic and neurotropic melanoma can be difficult. Although S100 protein stains a majority of these melanomas, the staining may be weak or focal. HMB-45, a more specific marker of melanoma, is frequently negative in desmoplastic and neurotropic melanoma. In order to aid the identification of desmoplastic and neurotropic melanoma, we stained 13 spindle cell melanomas (5 neurotropic melanomas, 5 desmoplastic melanomas, 3 spindle cell melanomas without either desmoplasia or neurotropism) with p75 NGF-R and compared the staining results with S100 and HMB-45. p75 NGF-R is the low affinity nerve growth factor receptor reported to be present on the surface of neural-crest-derived cells. Conventional melanoma as well as neurotized nevi, neurofibroma, spindle squamous carcinoma, atypical fibroxanthoma, dermatofibroma and scars were also stained with p75 NGF-R. p75 NGF-R stained all of the desmoplastic and neurotropic melanomas tested. In each of these cases, negative HMB-45 staining of the spindle cells was seen. In many cases the number and intensity of the spindle cells staining with p75 NGF-R was greater than with S100. Neurofibroma, neurotized nevi and focal cells in round cell melanoma also were stained with p75 NGF-R. All the squamous cell carcinomas, atypical fibroxanthomas, dermatofibromas and scars were negative for p75 NGF-R. Based on our results, p75 NGF-R may be useful as an additional confirmatory antibody in a melanoma panel, especially in differentiating desmoplastic and neurotropic melanomas from non-neural-crest-derived spindle cell lesions. We feel it also can be helpful in better identifying margins of excision of these melanomas. p75 NGF-R, like S100 protein, will not differentiate desmoplastic and neurotropic melanomas from other neural-crest-derived lesions.
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PMID:p75 nerve growth factor receptor staining helps identify desmoplastic and neurotropic melanoma. 879 54

The low affinity p75 neurotrophin receptor (p75NTR) is a cysteine-rich transmembrane glycoprotein which is frequently overexpressed in advanced stages of human melanoma. The biological consequences of this overexpression are unknown; however, it has recently been shown that p75NTR can enhance the invasive potential of melanoma cells in vitro. In the present study we examined cell lines established from normal human melanocytes and metastatic melanomas for expression of p75NTR mRNA and protein. The results showed that, compared with normal melanocytes, levels of p75NTR-specific protein were high in seven melanoma lines, markedly decreased in two melanoma lines and comparable in two melanoma lines. The conserved transmembrane domain of p75NTR was analysed for point mutations by single strand conformation polymorphism analysis and direct DNA sequencing. Identical point mutations were detected in the transmembrane domain of p75NTR in the two melanoma lines with reduced p75NTR protein expression, which resulted in the substitution of the uncharged amino acid Gly for the negatively-charged Asp.
Melanoma Res 1996 Oct
PMID:Mutation and expression of the low affinity neurotrophin receptor in human malignant melanoma. 890 97

We have recently reported that the nuclei of B16 melanoma cells are intensely stained with anti-rat vitronectin (Vn) antibody, which reacts with both mouse and rat Vn. In the present study, we characterized the protein immunoreactive with the antibody using NIH3T3 cells, whose nuclei were also stained with the antibody. Western blot analysis showed that a protein with an approximate molecular weight of 75 kDa (p75), which was distinct from Vn, existed in the nuclear fraction, and, more specifically, in the nuclear matrix fraction, of NIH3T3 cells. Screening of an NIH3T3 cDNA library resulted in the isolation of a nearly full-length cDNA clone encoding p75. A database search revealed that the cDNA represents a novel gene. The deduced amino acid sequence showed that the protein is 580 amino acids long and contains two C2H2-type zinc finger motifs and glutamic acid-rich domains in the C-terminal region. When a fusion protein of green fluorescence protein and p75 was expressed in NIH3T3 cells, fluorescence was preferentially observed in the nuclei, demonstrating that the protein has a nuclear localization signal. The p75 protein, termed ZAN75, exhibited DNA-binding activity in a zinc-dependent manner. Southern blot analysis demonstrated that the ZAN75 gene exists in a single copy in the mouse genome and that a closely related gene is also present in chicken, rat, and human. Northern blot analysis showed that the ZAN75 gene is ubiquitously expressed in adult mouse tissues. In the cell cycle of NIH3T3 cells, expression was low in the G0/G1 phase, increased during the G1 phase, and persisted during the S and G2/M phases, suggesting that ZAN75 plays a role in regulating cell growth.
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PMID:Cloning and characterization of a novel zinc finger protein that associates with nuclear matrix. 980 46

The biological basis for the general pharmacological resistance of human melanoma is unknown. A unique biochemical feature of the melanocyte is the synthesis of melanin, which leads to the generation of hydrogen peroxide and the consumption of reduced glutathione. This activity produces a state of chronic oxidative stress in these cells. We demonstrated previously that the expression of the c-jun family was dysregulated in metastatic melanoma cells compared with normal human melanocytes (D. T. Yamanishi et al., J. Invest. Dermatol., 97: 349-353, 1991). In the current investigation, we measured the levels of two major redox response transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein-1, in metastatic melanoma cells and normal melanocytes and their response to oxidative stress. The basal DNA-binding activity of NF-kappaB as measured by the electrophoretic mobility shift assay in metastatic melanoma cells was increased 4-fold compared with that of normal melanocytes. This level of binding was paralleled by a 1.5- to 4-fold increase in the expression of p50 (NF-kappaB1), p65 (Rel-A), and IkappaB-alpha as measured by Northern blot analysis. In contrast, the expression of p75 (c-rel) was markedly decreased (60%) in melanoma cells compared with normal melanocytes. Following oxidative stress produced by enzyme-generated H2O2, free H2O2, or incubation with buthionine sulfoximine, NF-kappaB binding activity increased 1.5- to 2.5-fold in melanoma cells (buthionine sulfoximine > H2O2), but only slightly in normal melanocytes. In contrast, activator protein-1 binding activity was unaffected or increased in normal melanocytes in response to oxidative stress, but was either unaffected or decreased in melanoma cells. These results suggest that the redox regulation of melanoma cells at the molecular level is fundamentally different from normal melanocytes and may offer a unique avenue for preventive or therapeutic intervention as well as new insights into the pathogenesis of melanocyte transformation.
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PMID:Activation of nuclear factor-kappa B in human metastatic melanomacells and the effect of oxidative stress. 1035 57

The role of growth factor receptors in regulating the progression of human melanocytes toward tumorigenicity and ultimately a malignant phenotype is poorly understood. In particular, the autocrine and paracrine influences that modulate cellular invasion and extracellular matrix (ECM)-degradative enzymes in melanoma cells remain undefined at the molecular level. The low-affinity p75 neurotrophin receptor (p75NTR), a cysteine-rich transmembrane glycoprotein, is frequently expressed in advanced stages of human melanoma, but the biological consequences of this expression are unknown. p75NTR can enhance the invasive potential of brain-metastatic melanoma cells in vitro. We have extended here these results and related the level of p75NTR in human metastatic melanoma cells to their invasive potential to target organs other than brain. Fluorescence activated cell sorting (FACS) analysis showed that 3 melanoma cell lines (SK-MEL-146, SK-MEL-119, 70W) had differential p75NTR contents, whereas SK-MEL-147 cells had elevated amounts of p75NTR. Two other melanoma cell lines (SK-MEL-94, SK-MEL-110) with point mutations in the p75NTR transmembrane domain had reduced (SK-MEL-94) or absent (SK-MEL-110) p75NTR. We also examined these cell lines for presence of TrkA receptor, the high-affinity receptor for nerve growth factor (NGF), the prototypic neurotrophin. No TrkA receptor expression was detected in any of the cell lines. The extent of p75NTR expression correlated with the capability of NGF to promote cellular invasion and with production of heparanase, an important ECM-degradative enzyme. Melanoma cells sorted for high p75NTR expression (p75NTR-H cells) had markedly greater (9- to 13-fold increase) invasive capabilities in response to NGF exposure than those sorted for low p75NTR expression (p75NTR-L cells). Additionally, NGF induced a 8- to 10-fold increase of heparanase activity in p75NTR-H cells. Thus, we propose that p75NTR-mediated trophic support profoundly affects melanoma cell invasion to neurotrophin-rich organs.
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PMID:Correlation of overexpression of the low-affinity p75 neurotrophin receptor with augmented invasion and heparanase production in human malignant melanoma cells. 1036 Aug 29

The neurotrophins (NTs) are a group of growth factors involved in the development of the nervous system and presumed to play a role in neural crest-derived tumours. The expression of three NTs (NGF, BDNF, and NT-3) and their receptors (NTRs; i.e. low-affinity pan-NT receptor p75, Trk-B, and Trk-C) was studied in frozen sections of benign and malignant cutaneous pigment cell lesions, using immunohistochemistry. In order to understand the possible role of these growth factors and their receptors in the progression of primary cutaneous malignant melanomas (PCMMs), their distribution in the radial (RGP) and vertical (VGP) growth phases was particularly studied. While most of the common acquired naevi were unreactive, Spitz and blue naevi showed scattered immunoreactive cells, especially for the p75 NTR. Dysplastic naevi, but not common naevi, expressed NT-3 in their junctional component. PCMM and melanoma metastases often showed a diffuse pattern of immunostaining. NT-3 was significantly more frequently expressed in the RGP of PCMMs than in the junctional component of benign naevi, whereas more extensive immunoreactivity for NGF was found in the VGP of PCMMs, compared with the RGP; metastases more frequently expressed NGF, BDNF, and Trk-B than PCMMs. Interestingly, neurotropic melanoma expressed all NTs/NTRs except Trk-B. These immuunohistochemical data confirm suggestions from previous in vitro studies that autocrine loops of certain NTs and their respective receptors may be involved in melanoma progression; in addition, NT-3 may be involved in the junctional growth of dysplastic naevi. The precise role of these growth factors in melanoma, however, will await further functional studies.
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PMID:Expression of neurotrophins and their receptors in pigment cell lesions of the skin. 1132 47

Seventeen cases of spindled melanomas and eleven cases of epithelioid melanomas were immunolabeled with various melanoma and Schwann cell markers. Standard melanoma markers included S100, HMB45, HMB50, tyrosinase, and Melan A. Schwann cell markers included the p75 neurotrophin receptor (p75NTR), glial fibrillary acidic protein (GFAP), and the L1 adhesion protein. The degree of immunocytochemical labeling was scored by levels of both intensity and pervasiveness. The results confirmed a distinct difference in labeling between epithelioid and spindled melanomas. The p75NTR was strongly expressed in spindled melanomas and weakly expressed in the epithelioid melanomas. The usual melanoma markers, including HMB45, HMB50, MelanA, and tyrosinase had the reverse pattern, being strongly expressed in virtually all epithelioid melanomas, but rarely expressed in the spindled variants. S100 was unique among the markers in being expressed by both epithelioid and spindled melanomas. Glial fibrillary acidic protein and L1 adhesion protein were expressed moderately, with preferential labeling of the spindled melanomas. The greatest immunophenotypic difference between spindled and epithelioid melanomas was the high abundance of p75NTR expression in spindled melanomas. The functional significance of the high level of p75 neurotrophin receptor expression may contribute to the high predisposition of perineural extension in the desmoplastic subset of spindled melanomas.
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PMID:The p75 neurotrophin receptor, relative to other Schwann cell and melanoma markers, is abundantly Expressed in spindled melanomas. 1148 18


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