Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-dose interleukin-2 (IL-2) immunotherapy can cause hypotension, respiratory distress, interstitial edema, and thrombocytopenia, similar to endotoxic shock. We have observed that IL-2 has no direct effect on coagulation factors in vitro, but it has been observed to alter the coagulant properties of vascular endothelium. Accordingly, we investigated the possibility that IL-2 infusions initiate plasma fibrinolysis and disseminated intravascular coagulation (DIC). We studied the clinical course, platelet count, and coagulation profile in response to IL-2 infusion in seven patients, two with metastatic melanoma and five with metastatic renal cell carcinoma. Every patient experienced hemodynamic instability and thrombocytopenia, and one patient suffered an unusual complication, mesenteric thrombosis. No patient had appreciable changes in the prothrombin time or the partial thromboplastin time, nor did factors V or VIII decline in the two patients observed. In four patients examined, we found decreased titers of Hageman factor (factor XII), high molecular weight kininogen, prekallikrein, and plasma thromboplastin antecedent, as if these had been consumed by reactions of the intrinsic pathway of thrombin formation. Circulating D-dimer fragments were found in the plasma of every patient at some point during each infusion cycle, and we observed decreased titers of plasminogen in the four patients just mentioned, suggesting that IL-2 infusions initiated fibrinolysis. Taken together, the clotting factor derangements and related toxicity phenomena cannot be ascribed firmly to DIC. Activation of the intrinsic (contact) system of coagulation, however, may provide one link between the vascular endothelial surface alterations caused by IL-2 infusions and the development of the systemic toxicity that resembles septic shock.
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PMID:Fibrinolysis, thrombocytopenia, and coagulation abnormalities complicating high-dose interleukin-2 immunotherapy. 198 12

Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells (B16-BL6 melanoma; ESb T-lymphoma) attach, invade, and penetrate confluent vascular endothelial cell monlayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the [35S]O4 = -labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The macrophages do not store the heparanase intracellularly but it is instead found pericellularly and requires a continuous cell-matrix contact at the optimal pH for maintaining cell growth. The degradation of [35S]O4 = -labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10 micrograms/ml), arteparon (10 micrograms/ml), and heparin at a concentration of 3 micrograms/ml. In contrast, other glycosaminoglycans such as hyaluronic acid, dermatan sulfate, and chondroitin sulfate as well as the specific inhibitor of exo-beta-glucuronidase D-saccharic acid 1,4-lactone failed to inhibit the degradation of sulfated proteoglycans in the subendothelial extracellular matrix. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. However, the following antiproteases--alpha 2-macroglobulin, antithrombin III, leupeptin, and phenylmethylsulfony fluoride (PMSF)--failed to inhibit this degradation process, and only alpha 1-antitrypsin inhibited the heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage heparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase, inhibited at concentrations of 1 and 3 micrograms/ml, respectively. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis.
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PMID:Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells. 380 31

We have previously reported that treatment with interleukin 1 (IL-1) induced the augmentation of lung tumor colonies by a human melanoma in nude mice. Here we have investigated the involvement of the alpha 4 beta 1 integrin, the very late antigen 4 (VLA-4) in this augmentation. A375M melanoma cells expressed high levels of VLA-4 and preferentially adhered to a surface coated with vascular cell adhesion molecule 1 (VCAM-1), the ligand for VLA-4 on activated endothelial cells. This adhesion was inhibited by treating tumor cells with saturating concentrations of mAb to VLA-4. The production of lung colonies was significantly enhanced in nude mice given an injection of IL-1 before A375M melanoma cells. Immunoperoxidase staining showed that VCAM-1 could be expressed on lung vascular endothelium of mice in response to IL-1. Pretreatment of melanoma cells with a mAb to VLA-4 completely abrogated the IL-1-induced augmentation of lung colonies. Using two metastatic melanoma clones (clones 2/4 and 2/60) that expressed different levels of VLA-4, we found that only VLA-4-bearing cells adhered to a VCAM-1-coated surface and formed enhanced numbers of lung colonies in IL-1-treated nude mice. This augmentation was inhibited by pretreating the tumor cells with anti-VLA-4 mAb. These results demonstrate, in vivo, the functional involvement of VLA-4 on melanoma cells in IL-1-mediated lung colony augmentation, most probably involving the interaction of tumor cells with VCAM-1 on activated endothelial cells.
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PMID:Involvement of the very late antigen 4 integrin on melanoma in interleukin 1-augmented experimental metastases. 752 37

A critical step in the metastatic spread of tumour cells is the interaction of circulating tumour cells with the vascular endothelium. We have investigated the role of CD44 and its variants in the adhesion of a human melanoma cell line (RPMI-7951) and a breast adenocarcinoma cell line (MDA-MB-231) to quiescent human umbilical vein endothelial cells (HUVEC) in vitro. Both tumour cell lines express CD44H, CD44A and CD44v9, while HUVEC express only CD44H. Pre-treatment of endothelial cell monolayers with a blocking monoclonal antibody against CD44H (MAb 5A4) reduced the adhesion of RPMI-7951 cells but not that of MDA-MB-231. In contrast, pre-treatment of both tumour cell lines with the same antibody had no effect on adhesion. Digestion of the CD44 ligand hyaluronic acid (HA) on RPMI-7951 cells significantly reduced adhesion to endothelial monolayers, while digestion of HUVEC HA had no effect. We conclude that CD44H expressed on the surface of quiescent endothelial monolayers mediates in part the adhesion of the metastatic melanoma cell line RPMI-7951 but not that of a breast adenocarcinoma line. It does so by acting as a receptor for HA on the tumour cell surface. Tumour cell CD44H and variants CD44A and CD44v9 do not appear to be involved in adhesion to endothelial cells.
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PMID:Endothelial CD44H mediates adhesion of a melanoma cell line to quiescent human endothelial cells in vitro. 862 Dec 36

Cells in tissues interact with each other and with the extracellular matrix as part of a structural and informational unit. During cancer progression, tumor cells participate in the formation of a neotissue involving other cells and matrix. We recently observed in melanoma an association between tumor and endothelial cells via an amorphous matrix containing free laminin. The pericytic location of melanoma cells in this angio-tumoral complex raised the question of an intramesenchymal migration of metastatic melanoma cells promoted by free laminin along the endothelium. However the respective roles of melanoma cells and endothelial cells in laminin secretion were not clear. In an attempt to clarify the latter issue, we injected into mice three human melanoma cells lines, one secreting laminin and two that did not, in order to identify the source of laminin secretion in the subsequent interactions between tumor cells and vascular endothelium. Using immunohistochemistry and electron microscopy we observed in all three cases an amorphous matrix containing laminin between tumor and endothelial cells. The fact that two cell lines did not secrete laminin suggests that the periendothelial/peritumoral laminin could be of endothelial origin. Given the presence of laminin alone during intramesenchymal angiogenesis and embryogenesis, we propose an analogous role for endothelial laminin in facilitating the migration of melanoma cells along the abluminal surface of the endothelium.
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PMID:Angio-tumoral laminin in murine tumors derived from human melanoma cell lines. Immunohistochemical and ultrastructural observations. 1068 99

Inhibition of cancer growth by resveratrol (trans-3,5,4'-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.
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PMID:Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma. 1573 13

Protease-activated receptor-1 (PAR-1) is a key player in melanoma metastasis with higher expression seen in metastatic melanoma cell lines and tissue specimens. cDNA microarray and Western blot analyses reveal that the gap junctional intracellular communication molecule connexin 43 (Cx-43), known to be involved in tumor cell diapedesis and attachment to endothelial cells, is significantly decreased after PAR-1 silencing in metastatic melanoma cell lines. Furthermore, Cx-43 promoter activity was significantly inhibited in PAR-1-silenced cells, suggesting that PAR-1 regulates Cx-43 at the transcriptional level. Chromatin immunoprecipitation studies showed a reduction in the binding of SP-1 and AP-1 transcription factors to the promoter of Cx-43. Both transcription factors have been shown previously to be required for maximal Cx-43 promoter activity. These results were corroborated by mutating the AP-1 and SP-1 binding sites resulting in decreased Cx-43 promoter activity in PAR-1-positive cells. Moreover, as Cx-43 has been shown to facilitate arrest of circulating tumor cells at the vascular endothelium, melanoma cell attachment to endothelial cells was significantly decreased in PAR-1-silenced cells, with this effect being abrogated after PAR-1 rescue. Herein, we report that up-regulation of PAR-1 expression, seen in melanoma progression, mediates high levels of Cx-43 expression. As both SP-1 and AP-1 transcription factors act as positive regulators of Cx-43, our data provide a novel mechanism for the regulation of Cx-43 expression by PAR-1. Indeed, Cx-43 expression was restored following PAR-1 rescue in PAR-1-silenced cells. Taken together, our data support the tumor promoting function of Cx-43 in melanoma.
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PMID:Overexpression of protease-activated receptor-1 contributes to melanoma metastasis via regulation of connexin 43. 1967 55

Activation of the coagulation system in malignancy enables tumor spreading and is thus associated with poor prognosis for the patient. In this study, we analyzed the in vitro mechanisms by which two human metastatic melanoma cell lines, MV3 and WM9, transform the vascular endothelium into a prothrombotic activated state. We show that both melanoma cell lines activate prothrombin due to tissue factor (TF) expression by showing that thrombin generation was blocked with a TF-neutralizing antibody and TF-siRNA. In addition, using the cysteine protease inhibitor E-64, we excluded the formerly described cancer procoagulant (CP) as a major factor contributing to thrombin generation. Furthermore, we describe a direct thrombin-independent response of endothelial cells (ECs) to MV3-derived supernatant as measured by rapid release of VWF. We also show that two clinically approved LMWHs, tinzaparin and enoxaparin, are effective inhibitors of thrombin generation and thrombin activity in plasma. Furthermore, our data indicate a protective effect of heparins on EC activation as shown by reduced VWF release in response to MV3 supernatant. These promising effects of heparins on the melanoma-induced thrombotic conditions justify further clinical investigations in the field of oncology.
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PMID:The mechanism of melanoma-associated thrombin activity and von Willebrand factor release from endothelial cells. 2050 48

Melanoma cells actively participate in tumor angiogenesis and vasculogenic mimicry. However, anti-angiogenic therapy in patients with melanoma has not shown a significant survival gain. Thus, new anti-melanoma angiogenic and vasculogenic drugs are highly desired. Using the metastatic melanoma cell line C8161 as a model, we explored melanoma vasculogenic inhibitors and found that lycorine hydrochloride (LH) effectively suppressed C8161 cell-dominant formation of capillary-like tubes in vitro and generation of tumor blood vessels in vivo with low toxicity. Mechanistic studies revealed that LH markedly hindered expression of VE-cadherin in C8161 cells, but did not affect expression of six other important angiogenic and vasculogenic genes. Luciferase assays showed that LH significantly impeded promoter activity of the VE-cadherin gene in a dose-dependent manner. Together, these data suggest that LH inhibits melanoma C8161 cell-dominant vasculogenic mimicry by reducing VE-cadherin gene expression and diminishing cell surface exposure of the protein.
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PMID:Lycorine hydrochloride inhibits metastatic melanoma cell-dominant vasculogenic mimicry. 2278 16

Therapy for cancer can be achieved by artificially stimulating antitumor T and natural killer (NK) lymphocytes with agonist monoclonal antibodies (mAb). T and NK cells express several members of the TNF receptor (TNFR) family specialized in delivering a costimulatory signal on their surface. Engagement of these receptors is typically associated with proliferation, elevated effector functions, resistance to apoptosis, and differentiation into memory cells. These receptors lack any intrinsic enzymatic activity and their signal transduction relies on associations with TNFR-associated factor (TRAF) adaptor proteins. Stimulation of CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNFR (GITR; CD357) promotes impressive tumor-rejecting immunity in a variety of murine tumor models. The mechanisms of action depend on a complex interplay of CTL, T-helper cells, regulatory T cells, dendritic cells, and vascular endothelium in tumors. Agonist mAbs specific for CD137 have shown signs of objective clinical activity in patients with metastatic melanoma, whereas anti-OX40 and anti-GITR mAbs have entered clinical trials. Preclinical evidence suggests that engaging TNFR members would be particularly active with conventional cancer therapies and additional immunotherapeutic approaches. Indeed, T-cell responses elicited to tumor antigens by means of immunogenic tumor cell death are amplified by these immunostimulatory agonist mAbs. Furthermore, anti-CD137 mAbs have been shown to enhance NK-mediated cytotoxicity elicited by rituximab and trastuzumab. Combinations with other immunomodulatory mAb that block T-cell checkpoint blockade receptors such as CTLA-4 and PD-1 are also promising.
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PMID:Agonist antibodies to TNFR molecules that costimulate T and NK cells. 2346 May 35


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