Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522102 (Melanoma)
 7,698 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the expression of the angiogenic factor vascular permeability factor) (VPF, also called vascular endothelial growth factor), in human melanoma cells in vitro and in vivo. Melanoma lines that develop tumors with a low metastatic potential in nude mice were found to have low expression levels of VPF in vitro, and the VPF expression levels in melanoma lines that yield highly metastatic xenografts were high. However, in vivo the correlation between VPF mRNA levels and the frequency of metastasis was lost; in all xenografts equally high levels of VPF mRNA were found, independent of the parental cell line. Hence, in vivo VPF gene expression was upregulated in the low expressing lines. The external factor responsible for this induction may be hypoxia, given that we found that low oxygen tension caused a (reversible) increase in the VPF mRNA levels in otherwise low expressing melanoma lines in vitro. A melanoma line with an inducible VPF expression was engineered into a line with a constitutive VPF expression. In the xenografts from this line a change in the vascular architecture was seen, indicating that the pattern or the level of VPF expression is important for tumor angiogenesis in melanoma xenografts.
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PMID:Vascular permeability factor expression influences tumor angiogenesis in human melanoma lines xenografted to nude mice. 753 47

Melanoma progression in general is characterized by an increase in both metastatic frequency and the vascular density of the tumour tissue. Although a direct correlation between these two parameters in individual cases seems to be lacking, it is clear that metastasis is invariably preceded by angiogenesis. One of the angiogenic factors that is produced by human melanoma cells is vascular endothelial growth factor (VEGF). To investigate the role of this factor in the angiogenic process in primary cutaneous melanoma we determined the mean vascular density and the presence of VEGF protein in biopsies of human lesions. The results were compared with those found in normal skin or uninvolved skin from melanoma patients. In addition, we studied morphological and antigenic features of the proliferating neovasculature. We show that (1) the mean vascular density gradually rises along with melanoma progression, (2) transition of horizontal to vertical growth phase melanoma is accompanied by induction of VEGF protein expression and accumulation of this factor in the stroma, (3) vertical growth phase melanoma is often organized in nodules separated by septa containing blood vessels, but without lymphatics, and (4) blood vessel lumina in vertical growth phase melanoma are separated from tumour nodules by two basal lamina containing collagen type IV and the endothelium shows activated morphology and focal expression of the adhesion molecule E-selectin. Our findings indicate that VEGF is a prominent angiogenic factor in melanoma angiogenesis. Although its expression is induced during progression, the effect of VEGF on the incidence of metastasis is probably indirect.
Melanoma Res 1997 Aug
PMID:Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis. 957 13

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.
Melanoma Res 1999 Feb
PMID:Prognostic value of tumour vascularity in metastatic melanoma and association of blood vessel density with vascular endothelial growth factor expression. 1033 35

Melanoma cells constitutively release intercellular adhesion molecule 1 (ICAM-1) as soluble ICAM-1 (sICAM-1), and its levels are elevated in melanoma patients and correlate with disease progression. However, this correlation is not absolute, suggesting that specific characteristics of neoplastic cells and/or ICAM-1-positive non-neoplastic cells may influence the amounts of circulating sICAM-1. In this study, we found a weak correlation (r = 0.55; r2 = 0.3) between sICAM-1 release by 40 metastatic melanomas (36 primary cultures and 4 cell lines), and ICAM-1 expression on neoplastic cells. In addition, melanoma-secreted interleukin-1alpha (IL-1alpha) (1/40) but not vascular endothelial growth factor (VEGF) (29/40), significantly (P < 0.05) up-regulated the shedding of sICAM-1 by human umbilical vein endothelial cells (HUVEC). This was completely abolished by IL-1alpha/beta neutralizing antibodies both at the protein and mRNA level. Altogether, our results suggest that (i) the extent of sICAM-1 release is distinctive for individual melanomas and can be independent of ICAM-1 expression; (ii) tumor endothelia may sustain levels of sICAM-1 in selected melanomas; (iii) melanoma-released VEGF does not affect ICAM-1 expression and sICAM-1 release by HUVEC. Melanoma-derived sICAM-1 inhibits cell-mediated cytotoxicity of melanoma cells; therefore, constitutive levels of sICAM-1 release and IL-1alpha secretion by individual melanomas can differentially influence tumor progression and the clinical effectiveness of cytotoxic-cell-based vaccines.
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PMID:In vitro analysis of the melanoma/endothelium interaction increasing the release of soluble intercellular adhesion molecule 1 by endothelial cells. 1041 67

The hyaluronan-rich matrix surrounding many tumours may facilitate tumour growth, invasion and angiogenesis, with the majority of this hyaluronan apparently being synthesised by normal fibroblasts, stimulated to do so by tumour cell-derived factors. Melanoma cell-conditioned medium (CM) stimulates up to a 6-fold increase in fibroblast glycosaminoglycan (GAG) synthesis, with the active factors being present in tumour CM ultrafiltration fractions > 30 kDa and < 1 kDa. These fractions are poorly active individually, but when recombined, the activity is substantially greater than the additive effect. The objective of this study was to identify the factors present in the ultrafiltration fraction > 30 kDa that produce a greater than additive effect with the fraction < 1 kDa in stimulating the incorporation of 3H glucosamine into fibroblast GAGs. A number of factors including basic fibroblast growth factor (bFGF), interleukin (IL)-1 beta, pleiotrophin, platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) failed to stimulate any significant increase in GAG synthesis, but when added to the < 1 kDa tumour CM fraction, both PDGF and to a lesser extent, bFGF, exhibited potent stimulating activities. Neutralising antibodies to PDGF and bFGF added to the melanoma CM decreased the fibroblast GAG-stimulating activity by 29% and 40%, respectively, in C8161 melanoma CM and by 47% and 45%, respectively, in Hs294T melanoma CM. The activities of PDGF-AA and PDGF-BB isoforms were indistinguishable, suggesting the PDGF-alpha receptor plays a role in the GAG-stimulatory response. Western analysis following treatment with PDGF, bFGF or melanoma CM revealed banding patterns for PDGF and melanoma CM that were similar. Immunoprecipitation of the PDGF-alpha receptor revealed it to be phosphorylated in fibroblasts treated with PDGF and melanoma CM, but not with control fibroblast CM. These studies suggest that PDGF plays an important role in the GAG-stimulating activity of the melanoma CM, but requires the presence of an as yet unidentified novel low molecular weight factor for full activity.
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PMID:Melanoma cell-derived factor stimulation of fibroblast glycosaminoglycan synthesis--the role of platelet-derived growth factor. 1044 2

Tissue factor (TF) is a transmembrane glycoprotein that complexes with factor VIIa to initiate blood coagulation. It was reported in an earlier study that expression of high levels of TF in a human melanoma cell line promotes metastasis, and that the cytoplasmic domain of TF is required for this metastatic effect. To analyze the functions of the cytoplasmic and extracellular domains of TF in metastasis, two TF mutants were constructed; in one mutant alanine was substituted for each of the three serine residues in the cytoplasmic domain, preventing phosphorylation; in the other mutant alanine was substituted for four key residues in the extracellular domain, preventing binding of factor VIIa and consequently eliminating the initiation of blood coagulation by the TF-VIIa complex. Melanoma lines expressing high levels of either mutant form of TF were weakly metastatic in SCID mice, indicating that phosphorylation of the cytoplasmic domain and formation of a complex with VIIa by the extracellular domain are required for the full metastatic effect of TF. It was also found that increasing TF expression in human melanoma cells does not increase expression of vascular endothelial growth factor or promote growth and vascularization of tumors derived from the melanoma cells, suggesting that TF acts by a mechanism other than angiogenesis to promote metastasis.
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PMID:Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule. 1045 59

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are both recognized as stimulators of migration and angiogenesis during the progression of melanoma. However, the timepoints during tumour progression at which the expression of these angiogenic factors is most essential is still controversial. Using immunohistochemical analyses, melanoma cells were found to express bFGF in 18 out of 19 primary tumours and in 13 out of 20 metastases. Eleven of the 19 primary tumours and 15 of the 20 metastases were found to contain VEGF-positive melanoma cells; five of the 19 patients showed no VEGF-expressing melanoma cells at all. This indicates that VEGF expression may be a later event in the progression of melanoma than bFGF expression. Reverse transcription-polymerase chain reaction (RT-PCR) analyses of the melanoma cell lines showed that all cell lines were positive for both bFGF and VEGF mRNA. CD31-positive endothelial cells were primarily seen in the metastases (17 out of 20). Only four of the primary tumours contained CD31-positive cells, but these tumours expressed bFGF as well as VEGF, indicating that both angiogenic factors may be important for the formation of vessels in tumours.
Melanoma Res 1999 Aug
PMID:Expression of basic fibroblast growth factor and vascular endothelial growth factor in primary and metastatic melanoma from the same patients. 1050 56

Dissemination of uveal melanomas is almost exclusively haematogenous, making angiogenesis of the tumour a prerequisite for the formation of metastases. Uveal melanomas must employ strategies to evade the immune system in order to escape immune surveillance. We therefore determined the expression of the following angiogenic and immunosuppressive factors in seven human uveal melanoma cell lines using reverse transcriptase-polymerase chain reaction (RT-PCR): secreted interleukin-1 receptor antagonist (sIL-1ra), interleukin (IL)-6, IL-8, IL-10, transforming growth factor (TGF)-alpha, TGFbeta, vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), angiopoietin-1 and angiopoietin-2. In addition, the secretion of sIL-1ra, IL-6, IL-8, IL-10, TGFbeta and VEGF was assayed by enzyme linked immunosorbent assay (ELISA). The potential of uveal melanoma cell lines to convert plasminogen to angiostatin was tested in an in vitro assay. All the factors except angiopoietin-1 were determined in one or more cell lines using RT-PCR, although these results were not necessarily confirmed by ELISA. Expression of VEGF and angiopoietin-2 was found in all seven cell lines. Production of angiostatin was observed in one cell line. All seven cell lines examined expressed angiogenic factors and most cell lines expressed immunosuppressive factors. The expression of VEGF and angiopoietin-2 in combination with a lack of angiopoietin-1 expression suggest high vascular remodelling capacity and could be of great relevance for the metastatic potential of uveal melanoma.
Melanoma Res 1999 Oct
PMID:Expression of angiogenic and immunosuppressive factors by uveal melanoma cell lines. 1059 10

Myofibroblasts infiltrate malignant liver tumors, although their pathogenic implications are unclear. Immunohistochemical detection of alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP), and CD31 and CD34 expression was used to analyze the contribution of myofibroblasts to angiogenesis in hepatic metastasis produced by intrasplenically-injected B16 melanoma (B16M). Because activated hepatic stellate cells (HSCs) are oxygen-sensing myofibroblasts producing vascular endothelial growth factor (VEGF), the effect of B16M and human A375 melanoma supernatants on VEGF production by immortalized rat HSC line T6 and primary cultured human HSCs also was studied under an hypoxic atmosphere mimicking a tumor microenvironment. Myofibroblast infiltration preceded endothelium recruitment in avascular micrometastasis and generated specific stroma for sinusoidal-type and portal-type angiogeneses. Thereafter, myofibroblasts and endothelial cells colocalized within both angiogenic patterns and their numerical densities correlated with metastasis development. Myofibroblasts often were GFAP-positive, suggesting an HSC origin. Melanoma supernatants stimulated VEGF messenger RNA and protein synthesis by HSCs. These effects were potentiated by hypoxia. VEGF up-regulation was accompanied by increased expression of cyclooxygenase type 2 (COX-2) and PGE2 synthesis. HSC production of VEGF decreased under COX-2 inhibition, whereas it was increased by exogenous PGE2. The high VEGF expression in HSCs induced by melanoma factors and hypoxia resulted in mitogenic, antiapoptotic, and motogenic stimulation of both murine hepatic sinusoidal endothelium and human umbilical vein endothelium. In conclusion, temporal and positional relationships evolve between myofibroblast and endothelium recruitment during metastasis development. Mechanistically, hypoxic induction of VEGF in tumor-activated HSCs may create a proangiogenic microenvironment, facilitating endothelial cell recruitment and survival during hepatic metastasis transition from an avascular to a vascular stage.
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PMID:Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. 1260 65

The aim of this study was to determine whether epidermal hyperplasia overlying cutaneous human melanoma is associated with increased tumour angiogenesis, tumour growth and the potential for metastasis. Forty-two surgical specimens of cutaneous human melanoma of different depths, each containing epidermis present in the tumour-free margin, were analysed by immunohistochemistry for the expression of the pro-angiogenic molecules basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) and the anti-angiogenic molecule interferon-beta (IFN-beta). The epidermis overlying intermediate and thick (1.0-10.0 mm), but not thin (0.5-1.0 mm), melanoma specimens was hyperplastic. Although the expression level of bFGF, VEGF and IL-8 in the epidermis directly overlying the tumour was similar to that in the distant epidermis, the expression of IFN-beta was significantly decreased in keratinocytes overlying intermediate and thick, but not thin, melanomas. The microvessel density was also increased in intermediate and thick specimens. Human melanoma cells were injected subcutaneously into nude mice. The resulting tumours were used to determine the association between overlying epidermal hyperplasia and neoplastic angiogenesis. Similar to human autochthonous melanomas, epidermal hyperplasia was found only over lesions produced by metastatic cells. Although there was no change in the expression of the pro-angiogenic molecules, the expression of IFN-beta was significantly decreased in the hyperplastic epidermis. Conditioned medium collected from cultures of the metastatic cell line induced in vitro proliferation of mouse keratinocytes, whereas conditioned medium collected from cultures of the non-metastatic cell line did not. Collectively, the data demonstrate that metastatic melanoma cells induce keratinocyte proliferation, leading to decreased expression of the negative regulator of angiogenesis, IFN-beta, and hence to increased angiogenesis.
Melanoma Res 2003 Aug
PMID:Epidermal hyperplasia overlying human melanoma correlates with tumour depth and angiogenesis. 1288 64


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