Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase-8 (MMP-8) is a neutral metalloproteinase of the fibrillar collagenase family that also includes MMP-1 and MMP-13. In contrast to the other collagenases, MMP-8 has a very limited tissue distribution, thought to be restricted to neutrophils and chondrocytes. In a previous study, we observed MMP-8 expression in human melanoma cells. This observation led us to assess in more detail the expression of MMP-8 in normal and malignant melanocytic cells. We found that MMP-8 was expressed by 11 out of 12 human melanoma cell lines tested and all 10 primary melanomas we examined, but was not expressed by four primary neonatal melanocyte strains. Since melanocytes arise from highly motile neural crest cells, we examined the hypothesis that MMP-8 might be expressed by neural crest cells. RT-PCR analysis of post-implantation mouse embryos indicated the presence of MMP-8 transcripts at E9.5. In situ hybridization and immunohistochemistry of mouse embryos between E9.5-E14.5 demonstrated MMP-8 expression in the surface ectoderm, neural crest cells and chondrocytes. MMP-8 was also detected in neural crest cell migration located in the circumference of the neural tube, branchial arches and the notochord. In addition, MMP-8 expression was observed between the somites, in circumscriptive areas of the developing brain, heart, and eye, and in the interdigital zones of the limbs. In summary, we found MMP-8 to be the first fibrillar collagenase expressed during development. In contrast to its restricted tissue expression post-partum, MMP-8 was present in multiple embryonic tissues, including neural crest cells. The production of MMP-8 by migrating neural crest cells may contribute to their ability to degrade fibrillar collagen matrices while in transit.
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PMID:Neutrophil collagenase (MMP-8) is expressed during early development in neural crest cells as well as in adult melanoma cells. 1173 Dec 74

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading extracellular matrix. Their role has been emphasized in tumor invasion, metastasis and tumor-induced angiogenesis. We studied the expression of collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) in 70 melanoma metastases obtained from 56 patients treated with combined chemoimmunotherapy. The patients were divided into 2 groups using a cut-off point of 0% for MMP-1 expression and 20% for MMP-3 expression. We found that patients with MMP-1 positive metastases (n = 38) had significantly shorter disease-free survival compared to patients with MMP-1 negative metastases (n = 18) (median 11.2 vs. 17.0 months, p = 0.0383). The disease-free survival of patients with high levels of MMP-3 expression in their metastases (> or = 20% positive tumor cells, n = 14) was also significantly shorter compared to patients with lower levels of expression (n = 42) (median 5.1 vs. 14.0 months, p = 0.0294). The expression of MMP-13 did not correlate to survival parameters. We also found that the presence of melanin, a pigment produced by melanocytes, correlated with high expression levels of MMP-1 (p = 0.0002), MMP-3 (p < 0.0001) and MMP-13 (p = 0.0009). The high expression levels of MMP-13 were also associated with the presence of visceral metastases (p = 0.0284). Our findings suggest that MMP-1 and -3 may have a special role in melanoma metastasis formation and thus they could be used to measure the biological activity of the disease.
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PMID:High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma. 1180 3

Melanoma exhibits heterogeneous growth patterns and widely varying sensitivities to multiple treatment modalities. This variability may reflect intrinsic genetic differences in factors giving rise to altered metabolism. Glucose is the primary energy source of tumours, including melanoma, and glucose transporter isoform 1 (Glut-1) and hexokinase are key rate-limiting factors in glucose metabolism. The levels of Glut-1 and total hexokinase activity were measured in 31 melanoma biopsies to determine the extent of tumour-to-tumour variability in these parameters. Relative Glut-1 levels were determined by Western immunoblot analysis using human anti-Glut-1 rabbit polyclonal antibody, and hexokinase activity was measured in the same samples by an enzymatic assay monitoring the reduction in the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP+) (in nmol NADP+ reduced/min per mg protein). All melanomas were from patients who had received no therapy prior to surgery. Immediately after excision, tumour biopsies were disaggregated to single cells by collagenase and DNase and frozen in liquid nitrogen. Thirty human melanomas exhibited a 22-fold variation in levels of Glut-1 and 29 exhibited a nine-fold variation in total cellular hexokinase activity. Glut-1 levels and hexokinase activity were not correlated with one another. The broad range in Glut-1 levels and hexokinase activity observed between melanomas suggests that these glycolytic rate-limiting parameters that influence the rate of glucose metabolism may contribute to the variability in melanoma response to treatment modalities.
Melanoma Res 2002 Feb
PMID:Variability in glucose transporter-1 levels and hexokinase activity in human melanoma. 1182 56

Tumor cell invasion and metastasis are a complex multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases. Tissue inhibitor of metalloproteinase-1 (TIMP-1) acts as a negative regulator of matrix metalloproteinases and thus prevents tumor cell invasion and metastasis by preserving extracellular matrix integrity. In the present study, we investigated whether increasing serum TIMP-1 levels by gene transfer would decrease experimental pulmonary metastasis of melanoma in C57BL/6 mice. Female animals bearing B16F10 melanoma pulmonary metastasis were injected intramuscularly twice per week with 100 microg of plasmid DNA encoding the human TIMP-1 cDNA (TIMP-1pDNA). Substantive levels of serum human TIMP-1 were observed 3 days after single injection and were found for 6 days thereafter. Pulmonary metastasis was significantly reduced in the mice following 4 weeks of TIMP-1 treatment as compared to the controls that were treated with the plasmid DNA vector alone. Further reduction of pulmonary metastasis and increase in survival were realized by intraperitoneal injection of 1000 U of IL-2 twice per week in combination with TIMP-1 treatment. In a parallel in vitro study, a 3-fold increase in TIMP-1 expression was observed in NIH3T3 cells after IL-2 treatment. Therefore, up-regulation of TIMP-1 expression by IL-2 likely contributed to the additive effect of IL-2 and TIMP-1 in reducing metastatic disease in the animal model. In conclusion, our findings support the potential of TIMP-1 gene therapy for the prevention of metastatic melanoma.
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PMID:Gene therapy of melanoma pulmonary metastasis by intramuscular injection of plasmid DNA encoding tissue inhibitor of metalloproteinases-1. 1185 29

Membrane-type metalloproteinase-1 (MT1-MMP) is a transmembrane metalloproteinase overexpressed in tumors, which plays a major role in the first step of pro-MMP-2 activation, leading to the generation of an intermediate 62 kDa species. The second step of MMP-2 activation that yields to the mature form is less understood and could involve an autocatalytic process and/or the activity of the plasminogen/plasmin system. Human melanoma A2058 cells, which express MMP-2 only in its pro-form, were used to determine the role of MT1-MMP during pericellular proteolysis and tumor progression. The induction of MT1-MMP overexpression by MT1-MMP cDNA transfection initiated the first step of MMP-2 activation. We provide evidence that a cooperation between the plasminogen/plasmin system and MT1-MMP endowed the cells with the ability to fully activate MMP-2 and with enhanced invasive properties in vitro. When injected subcutaneously in nude mice, MT1-MMP expressing clones induced rapid tumor growth and high tumor vascularization, while the control clones were poorly or not tumorigenic. Our data provide the first demonstration, in an experimental model, that MT1-MMP expression by tumor cells promotes tumor vascularization.
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PMID:Expression of membrane type 1 matrix metalloproteinase (MT1-MMP) in A2058 melanoma cells is associated with MMP-2 activation and increased tumor growth and vascularization. 1185 80

In previous experiments we have shown an enhanced expression of matrix metalloproteinase-1 (MMP-1) in fibroblasts obtained from the border of invasive melanoma in comparison to fibroblasts more distant from the tumour. In the study reported here we sought to determine whether melanoma-derived soluble factors are responsible for the stimulation of MMP-1 expression in fibroblasts. By real-time PCR and enzyme-linked immunosorbent assays, we demonstrated that the stimulation of fibroblasts with melanoma cell conditioned medium led to an increased expression of MMP-1 mRNA as well as MMP-1 protein, whereas melanoma cells themselves did not produce detectable amounts of MMP-1 protein. Basic fibroblast growth factor (bFGF) was detected as an important factor responsible for the enhanced expression of MMP-1 by fibroblasts after stimulation with melanoma cell conditioned medium. In a three-dimensional in vitro invasion assay, we demonstrated that fibroblasts are essential for melanoma cell invasion into a collagen I matrix. These findings support the hypothesis that stromal fibroblasts assist the invasion of melanoma cells through the extracellular matrix by producing elevated amounts of proteolytic enzymes after interaction with soluble factors (e.g. bFGF).
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PMID:Fibroblasts enhance the invasive capacity of melanoma cells in vitro. 1187 42

A lot of parallels have been described between invasion of malignant tumor cells and leukocyte movement during inflammatory responses. Concerning these similarities, we investigated the function of cytokine-suppressive anti-inflammatory drugs (CSAIDs), which act via inhibition of stress-activated MAP-kinases, in regulation of expression of proteolytic enzymes and in vitro invasion of malignant melanoma cells. The p38MAPK inhibitor SB203580 reduced matrigel invasion of MeWo cells by 60%, while the MEK-1 inhibitor PD98059 did not have any effect on invasion. Active p38MAPK was detected in MeWo cells by immunoblotting and confocal microscopy. Cells showed a constitutive expression of matrix-metalloproteinase (MMP)-2 as well as tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 mRNAs. Expression of MMP-1 or urokinase-type plasminogen activator (uPA) was not detected by Northern blot. Inhibition of p38MAPK by the specific inhibitor SB203580 resulted in downregulation of MMP-2 mRNA and protein levels as well as gelatinolytic activity, while expression levels of TIMP-1 and TIMP-2 mRNAs were not changed. The specific MEK-1 inhibitor PD98059 did not change expression of MMP-2 or TIMPs. Neither SB203580 nor PD98059 changed proliferation of cells. The results suggest that stress-activated protein kinases like p38MAPK are involved in regulation of expression of MMP-2 as well as in vitro invasion of malignant melanoma cells. Inhibitors of p38MAPK may be promising substances to interfere with a signaling cascade associated with invasion of malignant tumor cells.
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PMID:An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. 1191 86

Bisphosphonates (clodronate, alendronate, pamidronate and zoledronate) at therapeutically attainable non-cytotoxic concentrations inhibited MMP-3, -12, -13 and -20 as well as MMP-1, -2, -8 and -9, but not urokinase-type plasminogen activator (uPA), a serine proteinase and a pro-MMP activator. Dose-dependent inhibition was shown by three independent MMP assays. The inhibition was reduced in the presence of an increased concentration of Ca(2+) when compared to physiologic Ca(2+) concentration. Alendronate inhibited the in vitro invasion (Matrigel) of human HT1080 fibrosarcoma and C8161 melanoma cells, and the random migration of these malignant and endothelial cell lines capable of expressing MMPs and uPA. The concentration of alendronate required to inhibit 50% of the activity (IC(50)=40-70 microM) of MMPs corresponded to the IC(50) of down-regulation of in vitro invasion and migration. The ability of bisphosphonates to down-regulate the in vitro invasion and random migration was comparable or slightly better in relation to the selective gelatinase inhibitor CTTHWGFTLC peptide. Alendronate but not CTTHWGFTLC peptide promoted the adhesion of HT1080 fibrosarcoma and C8161 melanoma cell lines on fibronectin. Bisphosphonates are broad-spectrum MMP inhibitors and this inhibition involves cation chelation. Bisphosphonates further exert antimetastatic, anti-invasive and cell adhesion-promoting properties, which may prevent metastases not only into hard tissues but also to soft tissues.
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PMID:Bisphosphonates inhibit stromelysin-1 (MMP-3), matrix metalloelastase (MMP-12), collagenase-3 (MMP-13) and enamelysin (MMP-20), but not urokinase-type plasminogen activator, and diminish invasion and migration of human malignant and endothelial cell lines. 1198 68

EMMPRIN, which is identical to human basigin (CD147), interacts with fibroblasts and stimulates expression of MMPs, which play an important role in tumor invasiveness and metastasis. In the present study, we demonstrated that coculture of basigin-expressing human MM cells with dermal fibroblasts resulted in the induction of MMP-1, MMP-2, MMP-3 and MT1-MMP production by fibroblasts and of melanoma cell invasion through a reconstituted basement membrane. Antibody to basigin inhibited both the production of MMPs by fibroblasts and the invasiveness of melanoma cells. Expression of basigin and MMPs in MM and surrounding fibroblasts was examined immunohistochemically in 28 specimens from 18 MM patients without metastasis and 10 with metastasis, to investigate whether basigin plays a role in metastasis of MM in vivo. Basigin was expressed in melanoma cells but not in fibroblasts. MM with metastasis had significantly higher basigin expression compared to MM without metastasis. There were significant differences between MMs with and without metastasis in the expression of MMPs in both melanoma cells and fibroblasts. Expression of MMPs in fibroblasts was positively correlated with expression levels of basigin. These immunohistochemic findings indicate that MMPs might be expressed in fibroblasts as well as melanoma cells concomitantly with basigin, which was expressed in melanoma cells more frequently in MM with metastasis. Basigin is highly expressed in melanoma cells and may play an important role in their invasiveness and metastasis by stimulating surrounding fibroblasts to express MMPs.
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PMID:Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. 1199 41

Interleukin-8 (IL-8) has recently been shown to contribute to human melanoma progression by functioning as a mitogenic and angiogenic factor. In the present study, we investigated whether targeting IL-8 by a fully human anti-IL-8 antibody (ABX-IL8) could be a potential therapeutic strategy to control angiogenesis, growth, and metastasis of melanoma. The human melanoma cells A375SM (high IL-8 producer) and TXM-13 (intermediate IL-8 producer) were injected subcutaneously into nude mice, which were then treated with ABX-IL8 (1 mg/3 times weekly, i.p., for 3 weeks). Tumor growth of both melanomas in ABX-IL8-treated mice was significantly inhibited when compared with control IgG-treated animals. ABX-IL8 treatment also suppressed experimental metastasis when the melanoma cells were injected intravenously. IL-8 blockade by ABX-IL8 significantly inhibited the promoter activity and the collagenase activity of matrix metalloproteinase-2 in human melanoma cells, resulting in decreased invasion through reconstituted basement membrane in vitro. In vivo, ABX-IL8 treatment resulted in decreased expression of matrix metalloproteinase-2, and decreased vascularization (angiogenesis) of tumors concomitant with increased apoptosis of tumor cells. Moreover, in an in vitro vessel formation assay, ABX-IL8 directly interfered with the tubule formation by human umbilical vein endothelial cells. Taken together, these results point to the potential utility of ABX-IL8 as a modality to treat melanoma and other solid tumors either alone or in combination with conventional chemotherapy or other anti-tumor agents.
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PMID:Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. 1210 97


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