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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent progress in elucidating the complex and heterogeneous interactions between malignancy and coagulation or fibrinolysis reactions in humans has clarified the pathogenesis of disseminated intravascular coagulation that occurs with malignancy and has revealed evidence for two distinct pathways of growth regulation based on production by tumor cells of initiators of thrombin formation versus plasminogen activators. We have proposed a preliminary classification of tumors (see Table 2) based on these interactions. Type I tumors are those in which the tumor cells are associated with an intact coagulation pathway that leads to thrombin formation at the tumor periphery but in which the tumor cells lack u-PA. Examples of tumors in this category include SCCL, malignant melanoma, and renal cell carcinoma. Type II tumors are those in which the tumor cells express u-PA but lack an associated coagulation pathway leading to thrombin formation. Examples of type II tumors include prostate cancer, colon cancer, breast cancer, and N-SCLC. Type III tumors are those that express neither of these pathways, or exhibit some other pattern of interaction. Obviously, this formulation must be regarded as hypothetical. However, this concept fits with the limited data available to date from clinical trials. More importantly, this hypothesis can be tested further by means of intervention aimed at interrupting pathways relevant to specific tumor types. Characterization of additional tumor types by the methods described should permit amplification of this classification of tumors and other patterns of interaction may be defined. Exploration of the coagulation-cancer interaction holds considerable promise for gaining new understanding of both the coagulation mechanism and tumor biology. Most intriguing is the prospect that imaginative approaches to cancer treatment may be devised that are not only relatively nontoxic and low cost, but also effective.
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PMID:Pathways of coagulation/fibrinolysis activation in malignancy. 157 11

Seven different tumor cell lines (human melanoma SK MEL 28; hamster melanoma HM29; murine melanomas B16F10 and amelanotic melanoma B16a; human colon carcinoma HCT8; murine colon carcinoma CT26; and murine Lewis lung carcinoma) were treated with thrombin at 0.5-1 unit/ml and examined for their ability to bind to adherent platelets; HM29 was studied for its ability to bind to fibronectin and von Willebrand factor; CT26, B16F1, B16F10, and B16a were studied for their ability to form pulmonary metastasis after i.v. injection of thrombin-treated tumor cells; CT26 was studied for its ability to grow s.c. Five of 7 thrombin-treated tumor cell lines increased their adhesion to adherent platelets 2-to 3-fold. HM29 increased its adherence to fibronectin and von Willebrand factor 2- to 3-fold. CT26, B16F1, B16F10, and B16a increased experimental pulmonary metastasis 10- to 156-fold. Thrombin-treated CT26 cells demonstrated 2-fold greater growth in vivo after s.c. injection. The mechanism of enhanced adhesion of thrombin-treated tumor cells to platelets required the platelet integrin GPIIb-GPIIIa since it could be inhibited by agents known to block adhesion of ligands to GPIIb-GPIIIa (monoclonal antibody 10E5, tetrapeptide RGDS, disintegrin Albolabrin); as well as a "GPIIb-GPIIIa-like" structure on tumor cells since it could be inhibited by treatment of thrombin-treated tumor cells with 10E5 and RGDS. The thrombin effect on tumor cells was optimum at 1 h of incubation with thrombin, did not require active thrombin on the tumor cell surface, and did not require protein synthesis (not inhibited by cycloheximide). Thus, thrombin-treated tumor cells markedly enhance pulmonary metastasis. It is suggested that this may be secondary to thrombin-induced enhanced adhesion as well as growth of tumor cells.
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PMID:Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. 159 84

Monoclonal antibody H3/5-47 was raised against a human melanoma metastasis and recognizes an antigen expressed in the endothelial cells of all normal human organs as assessed by immunohistochemistry. Antigen expression is higher in venous than in capillary or arterial endothelia; capillary endothelia of different microvascular beds, such as skin, lung, gut or liver, may express varying amounts of this antigen. H3/5-47 antigen expression in the endothelia of diseased tissues (inflammatory diseases, neoplasias) largely reflects its expression pattern in normal tissues. As might be anticipated, the highest expression of H3/5-47 antigen is found in resting adult cutaneous and hepatic cavernous venous hemangiomas. In contrast, psoriatic vessels, characterized by hypertrophy and fenestrations, tend to express H3/5-47 antigen at a much lower density. In human umbilical vein endothelial cells, half the single donor cases show no expression of H3/5-47 antigen, while the rest express the antigen at relatively low densities in about half the cells. Treatment with interferon-gamma or thrombin, but not interleukin-1, lipopolysaccharide, endothelial cell growth factor or phorbolester, either enhances or induces de novo expression in cultured human umbilical vein endothelial cells within 24h; maximum expression of H3/5-47 antigen is induced by interferon-gamma within 72 h. H3/5-47 antigen is not similar to other antigens inducible in human umbilical vein endothelial cells such as HLA-DR, ICAM-1, HECA-452, Leu13, MCP-1 or gamma-IP-10. It is not specifically expressed in the endothelium as it may also recognize certain epithelia, peripheral nervous tissue and bone marrow-derived cell populations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoclonal antibody H3/5-47 recognizes an inducible cell surface antigen expressed differently in endothelium of normal and diseased tissues and in vitro. 162 58

Two phenotypic parameters, aberrant expression of protein kinase C and tumor cell-induced platelet aggregation (PA), have been correlated with abnormal growth behavior and metastatic potential of tumor cells. We recently observed that N,N,N-trimethylsphingosine (TMS) and N,N-dimethylsphingosine (DMS), but not sphingosine (SPN), had an inhibitory effect (via blocking of transmembrane signaling) on the growth of various human tumor cell lines in vitro as well as in vivo in nu/nu mice (K. Endo et al., Cancer Res., 51: 1613-1618, 1991). We therefore investigated the effects of TMS, DMS, and SPN on (a) PA induced by ADP and thrombin; (b) PA induced by melanoma cell line B16/BL6; and (c) experimental lung colonization as well as spontaneous lung metastasis of BL6 cells in syngeneic C57BL/6 mice. In experiments on agonist-induced PA, TMS inhibited PA and ATP secretion 5-fold more strongly than DMS or SPN. This effect may be based on the inhibition of Mr 47,000 platelet protein phosphorylation and/or inhibition of phosphatidylinositol turnover as a transmembrane signaling pathway in platelets. Tumor cell (BL6 melanoma)-induced PA and ATP secretion were also strongly inhibited by TMS, but not by DMS or SPN. Unlike ADP- or thrombin-induced PA, BL6 cell-induced PA was not inhibited by Calphostin-C (a potent protein kinase C inhibitor) or cilostazol (a potent inhibitor of PA based on inhibition of cyclic AMP phosphodiesterase). Since many previous studies suggested that the ability of tumor cells to induce PA is related to the degree of malignancy (e.g., metastatic potential) of tumor cells, we studied the effect of TMS on lung metastatic potential. Three independent sets of experiments, as described below, all showed clear inhibition of lung metastasis by administration of TMS: (a) i.v. coinjection of BL6 melanoma cells and TMS; (b) i.v. injection of TMS and, 1 h later, BL6 cells; (c) spontaneous metastasis to lung from s.c. BL6 tumor (TMS administered after establishment of tumor, followed by resection of tumor). In comparison to tumor growth inhibition produced by TMS or DMS, inhibition of melanoma metastasis by TMS is obvious at lower doses.
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PMID:Cell membrane signaling as target in cancer therapy. II: Inhibitory effect of N,N,N-trimethylsphingosine on metastatic potential of murine B16 melanoma cell line through blocking of tumor cell-dependent platelet aggregation. 165 77

Immunohistochemical techniques applied to fresh frozen sections of metastatic malignant melanoma tissue revealed abundant fibrinogen (or fibrin I) in perivascular areas throughout the tumor connective tissue stroma. Fibrin was readily detected in a focal distribution in the connective tissue around nodules of viable tumor. Staining for D-dimer of cross-linked fibrin (using an antibody that cross-reacted with fragment D of fibrinogen) coincided with staining for fibrin. Diffuse staining of tumor cell bodies was observed for Factor X, and Factor XIII ("a" subunit) was detected in scattered areas of connective tissue throughout the tumors. Factor VII was not detected, and only rare tumor cells stained for tissue factor. These results support the concept that a tumor cell-associated, thrombin-generating pathway exists in situ in malignant melanoma tissue that includes Factor X but neither tissue factor nor Factor VII. By contrast, tumor cell staining was observed rarely for urokinase and to a variable extent for tissue plasminogen activator.
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PMID:Malignant melanoma. Interaction with coagulation and fibrinolysis pathways in situ. 169 Sep 50

Glycoprotein IIb-IIIa (alpha IIb beta 3) and the vitronectin receptor (alpha v beta 3), two integrins that share the common beta 3 subunit, have been reported to function as promiscuous receptors for the RGD-containing adhesive proteins fibrinogen, vitronectin, fibronectin, von Willebrand factor, and thrombospondin. The present study was designed to establish a cell system for the expression of either GP IIb-IIIa or the vitronectin receptor in an otherwise identical cellular environment and to compare the adhesive properties of these two integrins with those of native GP IIb-IIIa and the vitronectin receptor constitutively expressed in HEL cells or platelets. M21 human melanoma cells lack GP IIb-IIIa and use the vitronectin receptor to attach to vitronectin, fibrinogen, fibronectin, and von Willebrand factor. To study the functional properties of GP IIb-IIIa in these cells, we transfected GP IIb into M21-L cells, a variant of M21 cells (Cheresh, D.A., and R.C. Spiro. 1987. J. Biol. Chem. 262:17703-17711), which lack the expression of functional alpha v and are therefore unable to attach to vitronectin, fibrinogen, and von Willebrand factor. Transfectants expressing GP IIb were isolated by immunomagnetic beads and surface expression of the GP IIb-IIIa complex was documented by FACS analysis and immunoprecipitation experiments performed with 125I-labeled M21-L/GP IIb cells. Comparative functional studies demonstrated that GP IIb-IIIa expressed in M21-L/GPIIb cells as well as native GP IIb-IIIa constitutively expressed in HEL-5J20 cells (an HEL variant lacking alpha v beta 3) mediated cell attachment to immobilized fibrinogen, but not to vitronectin or von Willebrand factor, whereas the vitronectin receptor expressed in M21 cells and HEL-AD1 cells (an HEL variant expressing alpha v beta 3) mediated cell attachment to fibrinogen, vitronectin, and von Willebrand factor. Similarly, PGl2-treated resting platelets attached to immobilized fibrinogen but not to vitronectin or von Willebrand factor, and this attachment could be inhibited by mAb A2A9 (directed against a functional site on the GP IIb-IIIa complex). However, in contrast to platelets, which adhered to vitronectin and von Willebrand factor after stimulation by thrombin or PMA, activation of the protein kinase C pathway in M21-L/GP IIb or HEL cells did not induce cell adhesion to vitronectin or von Willebrand factor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adhesive properties of the beta 3 integrins: comparison of GP IIb-IIIa and the vitronectin receptor individually expressed in human melanoma cells. 170 57

Activation of platelets with thrombin and other agonists causes a rapid increase in the phosphorylation of multiple proteins on tyrosine. To identify candidate protein-tyrosine kinases (PTKs; EC 2.7.1.112) that may be responsible for these phosphorylation events, we analyzed the expression of seven Src-family PTKs and examined the association of these kinases with known platelet membrane glycoproteins. Five Src-related PTKs were detected in platelets: pp60SRC, pp60FYN, pp62YES, pp61HCK, and two LYN products of Mr 54,000 and 58,000. The Fgr and Lck PTKs were not detected. Although strict comparative quantification of protein levels was not possible, pp60SRC was detected at higher levels than any of the other kinases. In addition, glycoprotein IV (GPIV, CD36), one of the major platelet membrane glycoproteins, was associated in a complex with the Fyn, Yes, and Lyn proteins in platelet lysates. Similar complexes were also found in two GPIV-expressing cell lines, C32 melanoma cells and HEL cells. Since PTKs appear to be involved in stimulus-response coupling at the plasma membrane, these results suggest that ligand interaction with GPIV may activate signaling pathways that are triggered by tyrosine phosphorylation.
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PMID:Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets. 171 82

Binding of iodine-125-labeled thrombin to fibrin clots from two siblings with juvenile stroke was 30% of normal, and abnormally high amounts of the radioligand (not adsorbed by fibrin) were found in the supernatant. In concordance with this finding, supernatants from the patients' fibrin clots caused abnormal enhancement of platelet aggregation, ATP secretion, and binding of 125I-fibrinogen to platelets exposed to subthreshold concentrations of ADP or epinephrine. Hirudin suppressed the enhancing effect of the patients' supernatants, and substitution of gamma-thrombin for alpha-thrombin led to normalization of platelet responses. Under some experimental conditions, degradation of the patients' fibrinogen by plasmin was impaired. However, the euglobulin lysis time, the rate of fibrin degradation by plasmin, and the lysis of the patients' plasma clots by human melanoma tissue-type plasminogen activator were normal. Patients' plasmas, as well as purified fibrinogen, showed a prolonged thrombin time (partially corrected by 10 mM CaCl2) and an impaired release of fibrinopeptide A in response to thrombin. However, the release in response to reptilase was normal, and the reptilase, ancrod, and thrombin coagulase times were within control (normal) values. In addition, the patients' fibrinogen showed normal polymerization of preformed fibrin monomers, normal sialic acid content, and normal binding to ADP or epinephrine-stimulated platelets. Our studies support the concept that thrombin and platelets play an important role in the occurrence of stroke in these patients and suggest a direction to be followed to identify the mechanism(s) contributing to thrombosis in subjects with abnormal fibrinopeptide release.
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PMID:A role for platelets and thrombin in the juvenile stroke of two siblings with defective thrombin-adsorbing capacity of fibrin(ogen). 182 31

A probe, recombinant antistasin, that reacts specifically with the activated form of factor X (Xa) was used in immunohistochemical procedures to detect cellular sites of Xa generation within intact tissues. Factor Xa was detected on tumor cells in small cell carcinoma of the lung, renal cell carcinoma, and malignant melanoma. Tumor-associated macrophages (but not tumor cells) expressed Xa in adenocarcinoma and squamous cell carcinoma of the lung, and Hodgkin's disease. Factor Xa in these locations corresponded to evidence reported previously for an intact coagulation pathway and thrombin formation associated with these tumor cells and macrophages. By contrast, only rare connective tissue cells stained for Xa in breast and colon cancer, tumor types shown previously to lack an intratumoral coagulation pathway and thrombin generation, and in normal liver, lung, breast, kidney, and placental tissues. Hepatocytes did not stain. These results suggest that such probes may be useful for studying the activation state of cell-associated factor X in situ within intact tissues.
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PMID:Cellular localization of activated factor X by Xa-specific probes. 187 16

Recombinant desulfatohirudin (r-hirudin), a highly specific inhibitor of thrombin, was examined to determine whether it would inhibit production of experimental lung metastasis by B16-F10 melanoma cells. In in vitro assays using mouse plasma, the high level of procoagulant activity in B16-F10 cells was significantly inhibited by r-hirudin in a dose-dependent manner. From 15 to 120 min after s.c. administration into C57BL/6 mice, r-hirudin (10 mg/kg) markedly prolonged clotting time in a time course pattern that directly correlated with that of blood distribution of 125I-labeled r-hirudin. The production of experimental lung metastasis by B16-F10 cells was significantly inhibited by r-hirudin administered s.c. at time points ranging from 120 min before to 60 min after tumor cell inoculation with the most significant effects found in mice given r-hirudin 15 or 2 min before the i.v. injection of tumor cells. The organ distribution of [125I]IdUrd-labeled tumor cells demonstrated a clear difference in the lungs of mice treated with r-hirudin and the lungs of control mice, and these differences directly correlated with the number of lung tumor colonies found 3 weeks later. The inhibition of lung metastasis was not due to direct antitumor effects of r-hirudin. These results suggest that inhibition of coagulation events by r-hirudin significantly inhibit experimental lung metastasis during a critical time of 60 min after the entry of tumor cells into the circulation.
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PMID:Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor. 187 99


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