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

Matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) play an important role in cancer cell invasion and metastasis. Recently, it was shown that the presence of activated MMP-2 correlates with melanoma progression in vitro. This activation involves coordinated expression of MMP-2, membrane-type 1 MMP (MT1-MMP), and TIMP-2. To investigate the expression profile of these enzymes in human melanoma, this study used tumour specimens obtained from both a human melanoma xenograft model, consisting of eight melanoma cell lines with different metastatic capacity in nude mice, and 60 fresh human cutaneous melanocytic lesions comprising all stages of melanocytic tumour progression. MT1-MMP and TIMP-2 mRNA and protein were present in all cell lines. Cell surface expression level of MT1-MMP, as determined by flow cytometry, was similar on all cell lines. In addition, western blot analysis revealed that both inactive and active MT1-MMP protein was expressed by all cell lines. MMP-2 mRNA and the pro-enzyme form of MMP-2 were expressed by all cell lines. Remarkably, the presence of functionally active MMP-2 was restricted to the most aggressive cell lines MV3 and BLM. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA isolated from subcutaneous xenografts revealed MT1-MMP and TIMP-2 mRNA expression in all lesions, whereas MMP-2 mRNA could be detected only in xenografts derived from the highly metastatic cell lines 1F6m, MV3, and BLM. Furthermore, immunohistochemistry demonstrated a marked increase of MMP-2 and MT1-MMP in MV3 and BLM xenografts, whereas TIMP-2 expression showed no evident correlation with metastatic capacity. In human cutaneous melanocytic lesions, MMP-2, MT1-MMP, and TIMP-2 mRNA were detectable by RT-PCR in all lesions. Expression of MMP-2 protein was not detectable, either in common and atypical naevi, or in melanoma in situ by immunohistochemistry. In these lesions, heterogeneous expression of MT1-MMP and TIMP-2 was present in melanocytic cells. In contrast, a large number of MMP-2 and MT1-MMP-positive tumour cells were observed in primary melanomas and melanoma metastases. Double staining experiments and immunohistochemistry on serial sections from the same lesions demonstrated that all tumour cells expressing MMP-2 also expressed MT1-MMP and TIMP-2. Finally, zymography of melanoma metastases revealed that MMP-2 was present in its functionally active form. This study demonstrates that expression of MT1-MMP and TIMP-2 and activation of MMP-2 are correlated with tumour progression both in the xenograft model and in human melanocytic lesions, strongly suggesting that these factors are required for melanoma invasion and metastasis formation.
 ...
PMID:Expression and activation of matrix metalloproteinase-2 (MMP-2) and its co-localization with membrane-type 1 matrix metalloproteinase (MT1-MMP) correlate with melanoma progression. 1087 45

Adenoviral E1 A proteins exhibit a strong tumor-suppressive activity in human tumor cells. However, E1 A is capable of transforming rodent and human cells in cooperation with other oncoproteins, such as activated RAS. Thus, the therapeutic use of wild-type E1A harbors the principal risk of enhancing tumor malignancy. This prompted us to construct E1A 13S cDNA-derived mutants that were unable to transform baby mouse kidney cells in cooperation with E1B and to test their tumor-suppressive activity in BLM human melanoma cells. Anchorage-independent growth in soft agar was reduced for those cell lines expressing the E1AdelCR2 mutant, which lacks the entire conserved region 2 (CR2) sequences, or for cells expressing the E1AcR3Ex2 mutant, which contains CR3 plus exon 2 sequences. In contrast, cell lines expressing the entire E1A wild-type (E1AWT) or only the exon 2 sequences (E1AEx2) grew like the parental BLM cells. Moreover, inoculation of nude mice with BLM cells or cells expressing E1AEx2 revealed large tumors after 2 weeks. In contrast, tumors derived from E1AdelCR2- or E1ACR3Ex2-expressing cells exhibited a substantial delay in tumor growth accompanied by a loss of E1A expression in the outgrown tumors. Cell lines expressing E1AWT showed an intermediate phenotype. Thus, expression of CR3 plus exon 2 sequences is sufficient to enhance both the antioncogenic properties and the therapeutic safety of E1A in our system.
 ...
PMID:Transformation-defective adenovirus 5 E1A mutants exhibit antioncogenic properties in human BLM melanoma cells. 1091 7

Tumor cell invasion and metastasis formation depend on both adhesive and proteolytic mechanisms. Previous studies have shown that expression of matrix metalloproteinase-2 and integrin alphavbeta3 correlate with melanoma progression. Recently, direct binding of matrix metalloproteinase-2 to alpha(v)beta3 was implicated in presenting activated matrix metalloproteinase-2 on the cell surface of invasive cells. In this study we investigated this, using the highly metastatic, alpha(v)beta3-negative melanoma cell lines MV3 and BLM, their beta3-transfected alpha(v)beta3 expressing counterparts, xenografts derived from these cell lines, and fresh human cutaneous melanoma lesions comprising all stages of melanoma progression. Expression and activation status of matrix metalloproteinase-2 were studied by reverse transcription-polymerase chain reaction, immunohistochemistry, western blotting, and zymographic analysis, respectively. Matrix metalloproteinase-2 protein expression in vitro was similar in both alpha(v)beta3-negative and alpha(v)beta3-positive cell lines Remarkable differences, however, exist in the localization of inactive and active matrix metalloproteinase-2. Soluble active matrix metalloproteinase-2 was detectable only in the conditioned medium of alpha(v)beta3-negative cell lines and undetectable in the alpha(v)beta3-positive cell lines. Conversely, active matrix metalloproteinase-2 was present exclusively on the cell surface of the alpha(v)beta3 expressing transfectants. Western blot analysis of other components that are involved in matrix metalloproteinase-2 activation showed that processing of proMT1-matrix metalloproteinase to the activated form was enhanced in beta3 transfectants, whereas secretion of tissue inhibitor of metalloproteinase-2 was decreased. In vivo, the presence of functionally active matrix metalloproteinase-2 was significantly higher in xenografts derived from the alpha(v)beta3 expressing MV3 and BLM cell lines. In human cutaneous melanoma lesions, neither matrix metalloproteinase-2 nor integrin alpha(v)beta3 is detectable in melanoma in situ as determined by immunohistochemistry. In contrast, the number of matrix metalloproteinase-2-positive and alphavbeta3-positive tumor cells was clearly increased in primary melanomas, and melanoma metastases. Double staining experiments and confocal laser microscopy demonstrated that the percentage of cells coexpressing matrix metalloproteinase-2 and alpha(v)beta3 increased in advanced primary melanomas and melanoma metastases. In addition, zymography showed that functionally active matrix metalloproteinase-2 was frequently present in melanoma metastases. In these lesions a high proportion of matrix metalloproteinase-2- and alphavbeta3-double-positive melanoma cells were detectable. Our study demonstrates that the presence of activated matrix metalloproteinase-2 correlates with expression of alpha(v)beta3 in human melanoma cells both in vitro and in vivo, and also in fresh human melanoma lesions. These findings strongly suggest that co-ordinated expression of both factors may be required for melanoma cell invasion and metastasis formation.
 ...
PMID:Coexpression of integrin alpha(v)beta3 and matrix metalloproteinase-2 (MMP-2) coincides with MMP-2 activation: correlation with melanoma progression. 1099 34

We investigated the effect of integrin alpha(v)beta(3) expression on the metastatic pattern of human melanoma cells in the central nervous system (CNS). For this purpose, we developed a hematogenous CNS melanoma metastasis model in nude mice using a modified internal carotid artery infusion technique. This protocol revealed 2 different patterns of CNS metastasis. The integrin alpha(v)beta(3)-expressing melanoma lines Mel57 and Zkr nearly exclusively produced metastases in the brain parenchyma, whereas cells of the BLM and MV3 lines, devoid of integrin alpha(v)beta(3) expression, preferentially metastasized to dura mater and leptomeninges. Treatment with hyaluronidase to obtain single BLM cell suspensions did not influence the metastatic pattern, indicating that this was not simply the result of entrapment of tumor cell aggregates in large-sized leptomeningeal vessels. The role of integrin alpha(v)beta(3) expression in the process of metastasis was tested by transfection of BLM, but did not lead to an altered pattern of metastasis. We did observe, however, slower growth of the transfected tumors, although the in vitro growth rate was unaltered, indicating a reduction in tumorigenicity. We conclude from our findings that CNS metastasis of melanoma cells in the mouse xenograft model occurs in at least 2 different but very reproducible patterns. Although it is predicted that adhesion of tumor cells to endothelial cells plays a role in this phenomenon, tumor cell integrin alpha(v)beta(3) expression per se does not explain the difference in metastatic behavior in the CNS. We assume that other, as yet unknown factors, must be involved.
 ...
PMID:The pattern of metastasis of human melanoma to the central nervous system is not influenced by integrin alpha(v)beta(3) expression. 1129 Oct 42

Chemokines are secreted into the tumor microenvironment by tumor-infiltrating inflammatory cells as well as by tumor cells. Chemokine receptors mediate agonist-dependent cell responses, including migration and activation of several signaling pathways. In the present study we show that several human melanoma cell lines and melanoma cells on macroscopically infiltrated lymph nodes express the chemokine receptors CXCR3 and CXCR4. Using the highly invasive melanoma cell line BLM, we demonstrate that the chemokine Mig, a ligand for CXCR3, activates the small GTPases RhoA and Rac1, induces a reorganization of the actin cytoskeleton, and triggers cell chemotaxis and modulation of integrin VLA-5- and VLA-4-dependent cell adhesion to fibronectin. Furthermore, the chemokine SDF-1alpha, the ligand of CXCR4, triggered modulation of beta(1) integrin-dependent melanoma cell adhesion to fibronectin. Additionally, Mig and SDF-1alpha activated MAPKs p44/42 and p38 on melanoma cells. Expression of functional CXCR3 and CXCR4 receptors on melanoma cells indicates that they might contribute to cell motility during invasion as well as to regulation of cell proliferation and survival.
 ...
PMID:Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. 1157 Dec 98

Recent reports suggest that elevated levels of plasminogen activator inhibitor-1 (PAI-1) may contribute to tumour progression. The studies reported here were designed to help elucidate PAI-1's contribution to the invasive and migratory phenotype. Antibodies to PA-1 dose-dependently, and significantly, inhibited the invasive and migratory potential of human HT1080 fibrosarcoma cells, as did an antibody to uPA and the plasmin inhibitor aprotinin. Invasion of the human melanoma cell line, BLM, was also attenuated by the anti-PAI-1 monoclonal antibody MAI-12. The non-invasive human melanoma cell line, IF6, which does not express uPA, provided further confirmation of PAI-1 and uPA's role as, upon transfection with uPA, this cell line attained an invasive phenotype, which was again attenuated by MAI-12. Although antibodies to PAI-1 did not affect the adhesion of HT1080 cells to vitronectin, the antibody to uPA reduced their attachment. Addition of exogenous PAI-1, however, prevented HT1080 cell adhesion (IC50 180 nM) and promoted cell detachment from vitronectin. Furthermore melanoma cells transfected with a uPA variant, which had an impaired interaction with PAI-1, were not invasive and had impaired binding to vitronectin. These data highlight the importance of a balanced proteolysis and suggest an additional role for PAI-1 distinct from its role in proteolysis. These data also suggest that uPA and PAI-1 may co-operate in the migratory process by respectively facilitating the attachment to, and subsequent detachment from, vitronectin in the extracellular matrix. These results support the clinical findings and indicate that modulation of PAI-1 activity may be of therapeutic benefit for the treatment of cancer.
 ...
PMID:Antibodies to PAI-1 alter the invasive and migratory properties of human tumour cells in vitro. 1159 1

Malignant melanoma is a tumor known for its uncontrollable growth and aggressive metastatic behavior. The mean survival time for patients with a metastatic melanoma is estimated to be less than 6 months, tumor cells being refractory to the conventional chemotherapy. A better understanding of the mechanisms regulating melanoma growth and progression might help increase the number of therapeutic options for this pathology. In this paper, we have shown that LHRH receptors are present in the BLM melanoma cell line, both at mRNA and at protein level; a potent LHRH agonist (LHRH-A; Zoladex) binds to these receptors with high affinity. BLM cells also express the mRNA for LHRH, indicating the presence of an autocrine LHRH-based system in melanoma cells. The treatment of BLM cells with LHRH-A dose-dependently inhibited cell proliferation; this effect was found to be specific because it was completely abrogated by the simultaneous treatment of the cells with a LHRH antagonist. Similar observations could be obtained in another melanoma cell line (Me15392). The activation of LHRH receptors, by means of LHRH-A, also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate through a Boyden's chamber in response to a chemotactic stimulus. These data represent the first report that 1) LHRH and LHRH receptors are expressed in melanoma tumor cells; and 2) the activation of tumor LHRH receptors reduces both the proliferation and the metastatic potential of melanoma cells. It is suggested that the expression of LHRH receptors might represent a new diagnostic marker for the detection and progression of melanoma. These receptors might also be considered as a possible molecular target for a hormone-based therapeutic approach to this tumor.
 ...
PMID:Locally expressed LHRH receptors mediate the oncostatic and antimetastatic activity of LHRH agonists on melanoma cells. 1216 12

Luteinizing hormone-releasing hormone (LHRH) is the key hormone in the control of reproductive functions. In recent years, it has become evident that LHRH might act as a growth modulatory factor in tumors of the reproductive system. We have shown that in prostate cancer cells LHRH is expressed, together with its receptors, to negatively regulate cell proliferation. In these cells, LHRH acts as an antimitogenic factor through the activation of the Gi-cAMP intracellular signaling pathway. More recently, we investigated whether an LHRH-based autocrine system might also be expressed in tumors that are not classically related to the reproductive tract, such as melanoma. Malignant melanoma is known to be characterized not only by a high proliferation rate, but also by an aggressive metastatic behavior. We have demonstrated that both LHRH and LHRH receptors are expressed in human melanoma cells (BLM and Me15392). Activation of LHRH receptors by means of a potent LHRH agonist (Zoladex) significantly inhibited cell proliferation. The LHRH agonist also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate in response to a chemotactic stimulus. These data indicate that: (a) in prostate cancer cells the LHRH receptor is coupled to a Gi-cAMP signal transduction pathway; (b) LHRH and LHRH receptors are also expressed in tumors that are not classically related to the reproductive system, such as melanoma; in melanoma cells, LHRH might act as an inhibitory factor on both cell proliferation and metastatic behavior. It is suggested that, in melanoma, LHRH receptors might represent a diagnostic marker and a possible molecular target for new therapeutic approaches for this pathology.
 ...
PMID:Inhibitory activity of luteinizing hormone-releasing hormone on tumor growth and progression. 1279 Jul 78

Invasion of melanoma cells into the dermal connective tissue is a major characteristic in the complex process of metastasis. Proteases play an important role in tumor cell invasion as these enzymes are able to degrade most components of the extracellular matrix (ECM), and thus enable cells to penetrate interstitial connective tissues and basement membranes. We developed an improved culture model that allows the detailed study of melanoma cell invasion in vitro. In this model, high (BLM) or low (530) invasive melanoma cells were seeded on the dermal side of dead deepidermized dermis (DDD) and cultured for 14 days at the air/liquid interface. The high invasive cells invaded the tissue, leading to dermal tumor formation, whereas the low invasive cells did not. Analysis of the enzymatic activity of gelatinases by in situ gelatin zymography at neutral pH revealed proteolysis only in those composites cultured with high invasive melanoma cells. Interestingly, in situ zymograms performed at more acidic conditions, favoring the activity of cysteine proteases, exhibited markedly enhanced and widespread gelatinolysis compared to neutral pH. Cysteine protease inhibitors (E-64 and leupeptin) significantly reduced invasion of melanoma cells into these composites. These results indicate an important role of cysteine proteases for tumor invasion.
 ...
PMID:Invasion of melanoma cells into dermal connective tissue in vitro: evidence for an important role of cysteine proteases. 1284 67

Tissue invasion by tumor cells involves their migration across basement membranes through activation of extracellular matrix degradation and cell motility mechanisms. Chemokines binding to their receptors provide chemotactic cues guiding cells to specific tissues and organs; they therefore could potentially participate in tumor cell dissemination. Melanoma cells express CXCR4, the receptor for the chemokine stromal cell-derived factor-1alpha (SDF-1alpha). Using Matrigel as a model, we show that SDF-1alpha promotes invasion of melanoma cells across basement membranes. Stimulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) activity by SDF-1alpha was necessary for invasion, involving at least up-regulation in the expression of this metalloproteinase, as detected in the highly metastatic BLM melanoma cell line. Moreover, SDF-1alpha triggered the activation of the GTPases RhoA, Rac1, and Cdc42 on BLM cells, and expression of dominant-negative forms of RhoA and Rac1, but not Cdc42, substantially impaired the invasion of transfectants in response to SDF-1alpha, as well as the increase in MT1-MMP expression. Furthermore, CXCR4 expression on melanoma cells was notably augmented by transforming growth factor-beta1, a Matrigel component, whereas anti-transforming growth factor-beta antibodies inhibited increases in CXCR4 expression and melanoma cell invasion toward SDF-1alpha. The identification of SDF-1alpha as a potential stimulatory molecule for MT1-MMP as well as for RhoA and Rac1 activities during melanoma cell invasion, associated with an up-regulation in CXCR4 expression by interaction with basement membrane factors, could contribute to better knowledge of mechanisms stimulating melanoma cell dissemination.
 ...
PMID:Stromal cell-derived factor-1alpha promotes melanoma cell invasion across basement membranes involving stimulation of membrane-type 1 matrix metalloproteinase and Rho GTPase activities. 1505 9


<< Previous 1 2 3 4 5 6 7 Next >>