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)

The role of platelets in cancer metastasis was studied by investigating the effects of the antiplatelet agents ticlopidine, diltiazem, dipyridamole and trapidil on artificial and spontaneous pulmonary metastases in mice. These agents were tested at their optimal inhibitory doses on adenosine diphosphate-induced platelet aggregation; namely, 100 mg/kg for ticlopidine, 2 mg/kg for diltiazem, 180 mg/kg for trapidil and 60 mg/kg for dipyridamole. At these doses, trapidil caused moderate inhibition of thrombin-induced platelet aggregation in mice, but the other agents had only slight effects. Artificial pulmonary metastasis was produced by inoculation of Lewis lung carcinoma (LLC) or B16 melanoma (B16) cells into C57BL/6 mice. For induction of spontaneous pulmonary metastases, these tumor cells were implanted subcutaneously into the footpads of mice. The resulting primary tumors of LLC and B16 were removed 9-10 and 17 days later, respectively. Artificial pulmonary metastases were inhibited significantly by all the antiplatelet agents tested. Spontaneous pulmonary metastases were markedly reduced only when these agents were given after removal of the primary tumor. The role of platelets is discussed with respect to thrombus formation in the lodgement of tumor cells and the participation of platelet-derived growth factor in the growth of metastatic foci.
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PMID:Effects of antiplatelet agents on pulmonary metastases. 672 29

A new platelet aggregation inhibitor compound, 5-(2-chlorobenzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine hydrochloride (ticlopidine), was examined for its inhibitory effects on blood-borne metastasis using three different rodent tumors (B16 melanoma, Lewis lung carcinoma, and rat ascites hepatoma, AH130). Ticlopidine was administered p.o. to the rodents. It inhibited the aggregation of platelets induced by adenosine diphosphate, thrombin, crude extract of AH130, and viable AH130 and B16 melanoma cells and also resulted in a significant decrease of pulmonary metastasis induced by i.v. injection of B16 melanoma and AH130. Spontaneous pulmonary metastasis of Lewis lung carcinoma was also inhibited by p.o. administration of ticlopidine. This new compound may be a useful agent for inhibiting platelet aggregation caused by various agents and for suppressing hematogenous pulmonary metastasis.
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PMID:Effects of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Ticlopidine), a platelet aggregation inhibitor, on blood-borne metastasis. 730 88

Cellular sites of coagulation activation within complex, intact tissues have been studied by immunohistochemical techniques. Hirudin, a specific and high affinity inhibitor of the active site of thrombin, together with antibody to hirudin were applied to sections of AMeX-fixed specimens of normal lung, kidney, placenta, freshly incised skin and unperturbed skin obtained at fresh autopsy; to rheumatoid synovial tissue; and to malignant tissue from a variety of tumor types. Staining for thrombin was observed selectively on pulmonary alveolar, rheumatoid synovial, and placental macrophages that express an intact extrinsic coagulation pathway. Staining was also observed restricted to the endothelium of capillaries in freshly incised skin but not in either unperturbed skin or in aged incisions. Staining of tumor cell bodies was observed in small cell carcinoma of the lung, renal cell carcinoma, and malignant melanoma tissues that we found previously to show tumor cell-associated procoagulant activity. This staining occurred commonly on cells within the tumor mass that were distant from stromal fibrinogen/fibrin. By contrast, tumor-associated macrophage but not tumor cell staining was seen in adenocarcinoma and squamous cell carcinoma of the lung, and little or no staining was seen colon cancer tissue. Negative controls in which either the hirudin probe or its antibody were omitted failed to show staining. These results are in accord with previous findings and suggest that such techniques may be useful for studying the cellular sites of thrombin generation in intact tissues. We postulate that administration of potent and specific thrombin antagonists, such as hirudin, to patients with relevant tumor types might be followed by homing of hirudin to tumor cells in vivo so that effects of local thrombin generation on malignant progression can be determined.
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PMID:Cellular localization of enzymatically active thrombin in intact human tissues by hirudin binding. 748 5

The Naka isoantigen is expressed on glycoprotein (GP) IV (CD36), a platelet membrane GP that has been identified as having a role in platelet interactions with collagen and thrombospondin and in binding Plasmodium falciparum-infected erythrocytes to endothelial cells and melanoma cells. We have studied normal platelets and Naka- platelets from two Japanese donors that have 1% of GPIV by concentration-dependent antibody binding and flow cytometry. We studied the adherence of normal and Naka- platelets to types I, III, and IV collagen in static and to type I collagen in flowing systems at high shear force. We have also studied aggregation of normal and Naka- platelets to type I collagen. Naka- platelets showed normal or increased aggregation to type I collagen and normal adhesion to types I, III, and IV collagen in the presence of Mg++ or EDTA. Platelet aggregation and adhesion were inhibited by the anti-alpha 2 beta 1 antibody 176D7 to the same extent in Naka- as in normal platelets. We also studied endogenous thrombospondin surface expression and found that thrombin-stimulated Naka- platelets expressed the same amount of thrombospondin as did normal platelets. From our studies with Naka- platelets, we cannot identify a definitive role for GPIV in platelet aggregation, in adhesion to types I, III, and IV collagen, or in endogenous thrombospondin binding to platelets.
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PMID:Platelet adhesion to collagen in individuals lacking glycoprotein IV. 751 49

The degradation of tenascin purified from human melanoma cells was examined by treatment with matrix metalloproteinases (MMPs) and serine proteinases. Among eight different types of proteinases examined, MMP-1, -3, and -7, cathepsin G and leukocyte elastase could digest tenascin, but MMP-2, MMP-9 and thrombin did not. This suggests that tenascin may be readily catabolized by extracellular matrix-degrading proteinases found in the pathophysiological conditions.
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PMID:Susceptibility of tenascin to degradation by matrix metalloproteinases and serine proteinases. 752 86

In this study we have investigated, using three different human melanoma cell lines (M1Do., M3Da., M4Be.). the varying capacity of melanoma cells to induce platelet aggregation in the presence or absence of inhibitors of ADP or thrombin. The expression levels of different integrins (alpha v, beta 3, alpha v beta 3, alpha IIb, alpha v beta 3) were evaluated by immunoprecipitation, binding and flow cytometry studies. The level of ADP in supernatants of melanoma cells were quantified by ADP bioassay and HPLC. Platelets were irreversibly aggregated by M3Da, as shown by electron microscopy, in contrast to M1Do, which induced a slow reversible aggregation. M4Be. did not induce platelet aggregation. In both cases, with M3Da. or M1Do., apyrase but not PPACK inhibited platelet induced aggregation. An anti-alpha v beta 3 monoclonal antibody (LYP18) or polyclonal antibody inhibited platelet aggregation. A similar number of LYP18 molecules bound to the surface of M1Do., M3Da. and M4Be. cell lines. Biological HPLC assays of ADP present in the supernatant of tumour cell lines showed the highest concentration of ADP to be secreted by M3Da., followed by M1Do., and none detected for M4Be. These results show that differences in in vitro aggregating potential of the three human melanoma cell lines are not related to low integrin expression levels but to their ability to generate ADP. Generation of ADP by human melanoma cells may act as important modulator of melanoma-platelet interactions.
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PMID:Human melanoma cell lines differ in their capacity to release ADP and aggregate platelets. 752 41

Modulation of cytoplasmic Ca++ concentration is a mechanism common to signal transduction pathways regulating many cellular phenomena, including the interactions of tumors with the hemostatic system. We have investigated the pro-aggregating and pro-coagulant activities of human tumor cell lines cultured in vitro and the ability of different platelet agonists to induce Ca++ transients in these cells. Cells of a malignant mesothelioma line activated platelets by a thrombin-dependent mechanism; on the contrary, HeLa cells, derived from a uterine cervical cancer, possessed ADP-dependent pro-aggregating activity, and DND-IA melanoma cells did not stimulate platelet aggregation. All cell lines showed a tissue-factor-like procoagulant property, more pronounced in mesothelioma cells. Furthermore, ADP was able to induce a transient increase in cytoplasmic Ca++ concentration in tumor cells from all lines; collagen showed this effect in mesothelioma cells and in HeLa cells, and thrombin was effective only in mesothelioma cells. PAF never induced Ca++ fluxes in any of the cell lines investigated. Finally, the calcium-channel blocker verapamil inhibited agonist-induced Ca++ transients in tumor cells and in vitro tumor-cell growth. These data may help to identify new possible mechanisms of the 2-way interaction of tumors with the hemostatic system.
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PMID:Effect of different platelet agonists on intracellular free Ca++ concentrations in human tumor cells: possible role in tumor growth. 762 70

The human melanoma cell line M24met expresses tissue factor, the cellular initiator of the blood coagulation cascade. Blocking of the coagulation pathways at the level of tissue factor, factor Xa, or thrombin inhibits hematogenous M24met metastasis in SCID mice, implicating a role for thrombin generation in this process. Dependent on cell surface tissue factor activity, M24met cells generate thrombin in vitro. Thrombin and the thrombin receptor agonist peptide TRP-14 activate a signaling pathway in M24met cells that involves an increase in intracellular calcium and induces cell proliferation. Immunofluorescence evidences expression of the signaling thrombin receptor on these cells. Thus, M24met melanoma cells express both the initiating cell surface receptor for the coagulation pathways and the central signaling receptor of the coagulation system, suggesting the in situ generation of proliferative signals which can contribute to the malignant phenotype.
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PMID:Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. 771 65

Adhesive interactions between cells and the subendothelial extracellular matrix take place at several stages during tumor progression and metastasis. We have previously demonstrated that thrombin possesses an active yet cryptic Arg-Gly-Asp (RGD) site which can be exposed in the presence of low concentrations of plasmin and cell-associated heparan sulfate proteoglycan. Thus, thrombin may act as a matrix-adhesive molecule via activation of the alpha v beta 3 integrin. We have now identified a 31 amino acid fragment as the minimal thrombin-generated cleavage product, which contains an active RGD site, following gel filtration analysis on FPLC Superdex 75 column. The role of membrane-associated heparan sulfate in thrombin conversion to an adhesive protein was demonstrated by using CHO cell mutants defective in various aspects of glycosaminoglycan synthesis. Incubation of both thrombin and a low concentration of plasmin on the surface of wild type CHO cells resulted in a typical digestion cleavage profile upon gel filtration. No cleavage products were observed when thrombin and a suboptimal plasmin concentration were incubated on monolayers of CHO cell mutants lacking heparan sulfate. Next, we examined the possible role of the thrombin RGD site during the progression of tumor development and metastasis. Toward this, we tested murine melanoma cells expressing low (B16-F1 cells) and high (B16-BL6 cells) lung colonization potentials in cell adhesion assays in vitro. Differential adherence capability of the cells was observed: while high attachment levels of B16-BL6 cells were obtained, the low metastatic B16-F1 cells did not adhere to thrombin RGD. Antibodies raised against the RGD site in thrombin specifically recognized thrombin digested with plasmin, but were unable to interact with native thrombin or prothrombin and inhibited potently B16-BL6 melanoma cell adhesion. Furthermore, the antibodies failed to recognize RGD in other adhesive plasma proteins such as vitronectin, fibrinogen, or fibronectin. Provided that the RGD-containing fragments of thrombin are widely distributed throughout the vascular system, they may have a significant role during tumor progression and dislodgement of metastatic cells. The development of RGD mimetics and/or specific antibodies might thus be applied to inhibit a critical step in metastatic spread.
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PMID:The involvement of thrombin RGD in metastasis: characterization of a cryptic adhesive site. 774

Previous work demonstrated that alpha-thrombin promoted tumor cell adhesion to endothelium and extracellular matrix as well as enhanced the metastatic capacity of tumor cells. This study was initiated to investigate whether the thrombin effect on tumor cells is mediated through the "tethered ligand" thrombin receptor. RT-PCR analysis using primers based on the human thrombin receptors detected mRNA in human colon adenocarcinoma cells (clone A), whose authenticity was confirmed by Southern hybridization. The presence of thrombin receptor mRNA in rat (W256 carcinosarcoma) and mouse (melanoma) tumor cells was demonstrated by RT-PCR/Southern blotting using species-specific PCR primers. Sequencing of the PCR fragment of clone A cells revealed complete homology with the reported human cDNA sequence. Subsequently, tumor cells derived from three species, i.e., human, rat, and mouse, were found to express the thrombin receptor protein as revealed by immunoblotting using ligand peptide-derived mAb ATAP138, whose reactivity towards the M(r) approximately 66,000, potential thrombin receptor was blocked by preincubating the antibody with the immunogen peptide SFLLRNPNDKYEPF (TRP 14). Finally, peptides TRP 14 and TRP 7 (SFLLRNP), but not TRP 5 (FLLRN), were found to mimic alpha-thrombin in stimulating tumor cell adhesion to fibronectin, suggesting that the thrombin receptors expressed on solid tumor cells are biologically functional.
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PMID:Solid tumor cells express functional "tethered ligand" thrombin receptor. 783 43


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