Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial extracellular matrix (ECM) is associated with degradation of heparan sulfate (HS) by a specific endoglycosidase (heparanase) activity. The enzyme is released from intracellular compartments (i.e., lysosomes, specific granules) in response to various activation signals (i.e., thrombin, calcium ionophore, immune complexes, antigens, mitogens), suggesting its regulated involvement in inflammation and cellular immunity. In contrast, various tumor cells appear to express and secrete heparanase in a constitutive manner, in correlation with their metastatic potential. Heparanase enzymes produced by different cell types may exhibit different molecular properties and substrate cleavage specificities. The platelet enzyme appears also in a latent form. It can be activated by tumor cells and thereby facilitate their extravasation in the process of metastasis. Degradation of ECM-HS by all cell types was facilitated by a proteolytic activity residing in the ECM and/or expressed by the invading cells. This proteolytic activity produced a more accessible substrate for the heparanase enzymes. Heparanase-inhibiting, nonanticoagulant species of heparin markedly reduced the incidence of lung metastasis in experimental animals. These species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Heparanase activity expressed by intact cells (i.e., platelets, mast cells, neutrophils, lymphoma cells) was found to release active HS-bound basic fibroblast growth factor from ECM and basement membranes. Heparanase may thus elicit an indirect neovascular response in processes such as wound repair, inflammation and tumor development. The significant anticancerous effect of heparanase-inhibiting molecules may therefore be attributed to their potential inhibition of both tumor invasion and angiogenesis. Both normal leukocytic cells and metastatic tumor cells can enter the bloodstream, travel to distant sites and extravasate to the parenchyma at these sites. We suggest that heparanase is utilized for this purpose by both types of cells. Other functions (i.e., enzyme activities, adhesive interactions, chemotactic and proliferative responses) of metastatic tumor cells seem to mimic the equivalent functions of leukocytes as they migrate across blood vessels to gain access to sites of inflammation.
Invasion Metastasis 1992
PMID:Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. 139

Nearly all patients with cancer manifest laboratory evidence of hypercoagulability and some develop clinical thromboembolic disease (TED). Routine laboratory studies of blood coagulation have been performed in several large, prospective trials of the use of anticoagulant drugs in cancer treatment. The results of these studies, as well as data from several smaller studies of more sensitive tests of hypercoagulability [e.g. fibrinopeptide A (FPA); thrombin-antithrombin (TAT) complexes; prothrombin fragment F1 + 2)], indicate that the levels of some clotting proteins parallel disease activity. However, no studies of sound methodologic design have yet been performed to indicate that any of these tests of blood coagulation can serve as adequate predictors of TED in patients with cancer. In addition to the important role played by tumor-related procoagulants, several other mechanisms may be involved in the pathogenesis of thromboembolic events in patients with cancer, including stasis and endothelial damage. Considerable variability in the relative importance of these mechanisms in the pathogenesis of TED may exist among patients with different types of cancer. The risk for TED associated with surgical procedures in cancer patients is substantial and prophylactic antithrombotic therapy should be considered for most of these patients. Chemotherapy and hormonal therapy of cancer probably increases the likelihood of TED, particularly in those subjects with indwelling venous catheters. This risk has been particularly well-studied in patients with breast cancer treated with tamoxifen plus cytotoxic drugs. The pathogenic mechanisms may be complex but vascular injury is likely as a proximate cause of venous access catheter thrombosis and can be prevented with low dose coumadin therapy. The utility of low dose coumadin anticoagulation in reducing the risk for TED during breast cancer treatment is unknown but is currently being tested in a large, multiinstitutional study. Since chronic coumadin anticoagulation of cancer patients, and single pulse dose heparin prior to intravenous chemotherapy, both prevent thrombin generation, these agents may be of use in reducing the risk of chemotherapy-associated thrombosis. Prophylactic anticoagulation should be considered for high risk patients.
Cancer Metastasis Rev 1992 Nov
PMID:Hemostatic alterations in cancer patients. 142 16

A volume of data that has accumulated for over a century has suggested that fibrin may facilitate the persistence and progression of malignancy. Techniques that have been developed recently have shown that fibrin is indeed a component of the connective tissue stroma in human malignancy but in only a few tumor types. However, therapeutic intervention studies with drugs that limit thrombin activity or enhance fibrinolysis have shown favorable clinical effects in at least one such tumor type. These favorable findings affirm the concept that cause-and-effect relationships do, in fact, exist between thrombin generation with fibrin formation and tumor progression, and suggest that a rational basis exists for the design of future drug intervention trials that target reactions relevant to specific tumor types. These findings also provide a basis for the design of experiments capable of defining further the role of fibrin in the integrity of these tumor types. Because fibrinogen is found much more commonly than fibrin in the connective tissue of a variety of human malignancies, attention might reassumably be directed to determining the possible contribution of this molecule as well as of fibrin to tumor progression.
Cancer Metastasis Rev 1992 Nov
PMID:The role of fibrin in tumor metastasis. 142 19

Blood vessels and lymphatics are the most important pathways for dissemination of cancer cells but the entry and exit of these cells into and from the vasculature requires that they pass through barriers formed by the endothelium and its basement membrane. This review summarizes evidence that this step in metastasis can be regulated by microenvironmental influences which alter the properties of this barrier. These phenomena can be attributed to both 'passive' and 'active' responses of the endothelium. The microvasculature is susceptible to perturbation from environmental agents, host cells and cancer cells. There is clinical and experimental evidence that this can upregulate the metastatic process. Using established animal models of pulmonary microvascular injury it has been shown that endothelial damage promotes the localization and metastasis of circulating cancer cells to the lung and that this effect is lost after endothelial repair. Oxidative stress is an effector of vascular damage in several of the experimental models. While endothelial cells appear to be directly susceptible to free radical attack, basement membranes are not. However, oxidative injury of endothelial cells causes release of proteases which can then degrade the basement membrane. This event is associated with generation of tumor cell chemoattractants and enhances cancer cell invasion of vascular basement membranes in vitro. Vascular endothelial cells are also susceptible to stimulation by systemic mediators including cytokines, thrombin, or endotoxin which induce a series of active responses in the vessel wall. These perturbed endothelial cells synthesize and express cell surface adhesion molecules which can interact with cancer cells. They also release chemoattractants which stimulate cancer cell motility. We postulate that such responses endow the vessel wall with the potential to act as a determinant of metastatic rate.
Cancer Metastasis Rev 1992 Nov
PMID:Cancer cell interactions with injured or activated endothelium. 142 23

Clinical trials of drugs that influence coagulation and fibrinolysis pathways have been undertaken in patients with malignancy because these pathways are capable of influencing malignant progression. The validity of this concept was originally confirmed in experimental animal models of malignancy. Earlier pilot studies in human disease have been succeeded by definitive prospective randomized clinical trials that have revealed heterogeneity of responsiveness to anticoagulant and fibrinolytic agents that may be attributable to differences in mechanisms of interaction of the tumor cells of various types of malignancy with these pathways in vivo. In certain tumor types studied thus far, increased tumor response rates and prolongation of survival have been observed that suggest the possibility that substantial benefit may be realized from this treatment approach in patients with malignancy. In addition, the availability of newer and potentially more effective therapeutic agents holds promise for even greater gains in previously tested tumor types. The ability to design treatment regimens that correspond to defined mechanisms that pertain to specific tumor types should permit future studies to be designed rationally. Current data suggest that anticoagulant and fibrinolytic agents might reasonably be tested in tumor types characterized by the existence of a tumor cell-associated coagulation pathway with thrombin generation and conversion of fibrinogen to fibrin (such as small cell carcinoma of the lung). By contrast, protease inhibitors might reasonably be tested in tumor types characterized by expression of tumor cell plasminogen activators. Expansion of current views on the possible role of antithrombic drugs in cancer therapy is justified. For example, antithrombotic drugs classified as non-steroidal anti-inflammatory agents may inhibit carcinogenesis while polyanionic drugs with anticoagulant properties, such as suramin and heparin, may inhibit growth factor interactions with cells. Intriguing new opportunities clearly exist for interactions between clinical and basic investigators that may provide both novel biologic insights and improved patient care.
Cancer Metastasis Rev 1992 Nov
PMID:Clinical trials with anticoagulant and antiplatelet therapies. 142 26

Coagulation disorders are frequently detected in patients affected by different tumours even though clinical symptoms occur in a very small percentage of such subjects. Coagulation processes are probably involved in the mechanism of metastatic spread. We assayed the plasma levels of thrombin-antithrombin III (TAT) complexes in a group of 276 patients with several tumours in different stages in order to achieve a better understanding of the complex interactions between coagulation disorders and either tumour growth or metastatic spread. High levels of TAT complexes were found in 51% of localized, 66.3% of metastatic and 58.3% of patients with no evidence of disease; a statistically significant difference was observed comparing metastatic cancer either with localized (p < 0.00015) or with free-of-disease (p < 0.004) groups. Gastrointestinal tract neoplasms showed higher levels of TAT complexes in the metastatic than in the localized group. No difference was seen between small-cell and non-small-cell lung-localized cancer. Our results confirm the frequent coexistence of cancer and subclinical blood coagulation disorders. The evidence of higher levels of TAT complexes in metastatic cancer than in the other groups could be related to the mechanisms involved in tumour spread.
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PMID:Latent coagulation disorders evaluated by the assay of plasma thrombin-antithrombin III complexes in a large series of 'solid tumours'. 146 80

Recent studies have revealed a role for platelets and the platelet-adhesive proteins, fibronectin and von Willebrand factor (vWF) in platelet-tumor cell interaction in vitro and metastasis in vivo. The present report documents the effect of thrombin treatment of platelets on this interaction in vitro and in vivo. In vitro, thrombin at 100-1,000 mU/ml maximally stimulated the adhesion of six different tumor cell lines from three different species two- to fivefold. As little as 1-10 mU/ml was effective. The effect of thrombin was specific (inhibitable by hirudin, dansyl-arginine N-(3-ethyl-1,5 pentanediyl) amide and unreactive with the inactive thrombin analogue N-P-tosyl-L-phenylchloromethylketone-thrombin and D-phenylalanyl-L-propyl-L-arginine chloromethylketone-thrombin (PPACK-thrombin), and required high-affinity thrombin receptors (competition with PPACK-thrombin but not with N-P-tosyl-L-lysine-chloromethyl-ketone-thrombin). Functionally active thrombin was required on the platelet surface. Binding of tumor cells to thrombin-activated platelets was inhibitable by agents known to interfere with the platelet GPIIb-GPIIIa integrin: monoclonal antibody 10E5, tetrapeptide RGDS and gamma chain fibrinogen decapeptide LGGAKQAGDV, as well as polyclonal antibodies against the platelet adhesive ligands, fibronectin and vWF. In vivo, thrombin at 250-500 mU per animal increased murine pulmonary metastases fourfold with CT26 colon carcinoma cells and 68-413-fold with B16 amelanotic melanoma cells. Thus, thrombin amplifies tumor-platelet adhesion in vitro two- to fivefold via occupancy of high-affinity platelet thrombin receptors, and modulation of GPIIb-GPIIIa adhesion via an RGD-dependent mechanism. In vivo, thrombin enhances tumor metastases 4-413-fold with two different tumor cell lines.
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PMID:Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo. 184 69

Current evidence indicates that the localization and extravasation of neutrophils is a complex process involving several adhesion molecules with apparently distinct functions, and a highly coordinated and dynamic interplay between the neutrophil and the endothelial cell that is influenced by the shear forces present at the interface between these two cell types. Chemotactic stimulation of the neutrophil not only induces directed locomotion but markedly alters the surface expression and functions of the neutrophil adhesion molecules, having both an upregulating and downregulating influence. Cytokines such as interleukin 1 induce the synthesis and surface expression of endothelial adhesion molecules such as ICAM-1 and ELAM-1, and stimuli such as thrombin and histamine induce the rapid mobilization to the endothelial surface of another adhesion molecule, GMP-140. Transendothelial migration of neutrophils in most settings both in vitro and in vivo appears to require CD18 integrins on the neutrophil and ICAM-1 on the endothelial cells. This is most clearly demonstrated by the genetic deficiency of CD18 in humans, dogs and cattle, where neutrophil extravasation at most inflammatory sites is almost completely absent. Though the coordinated functions of the various neutrophil and endothelial adhesion molecules are highly efficient in promoting neutrophil extravasation, there has been relatively little investigation of their utilization in tumor cell dissemination. Recent results indicate that such studies may prove fruitful. For example, some adenocarcinoma cell lines express the complex carbohydrate (sialyl Lewis x) recently shown to be a ligand for ELAM-1.
Cancer Metastasis Rev 1991 May
PMID:PMN adhesion and extravasation as a paradigm for tumor cell dissemination. 191 73

Immunotherapy with Interleukin-2 (IL-2) and LAK cells has shown antitumoral activity in metastatic cancer patients. So far, thrombocytopenia is the major side effect reported in hemostasis. We have studied coagulation parameters in 6 patients treated with r-Met Hu IL-2 [ala-125]. In each case, we have observed a significant fall in prothrombin time, fibrinogen, protein C, anti-thrombin III, plasminogen, alpha 2-antiplasmin and all of the clotting factors except factor VIII. There was a significant increase in the activated thromboplastin time. No significant modifications of the D-Dimer test, fibrin-fibrinogen degradation products (FDP) and thrombin time were observed. Our data suggest that r-Met Hu IL-2 [ala-125] could interfere with the hepatic synthesis of the clotting factors and their inhibitors.
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PMID:Blood coagulation abnormalities during adoptive immunotherapy with interleukin-2 (r-Met Hu IL-2 [ala 125]). 200 36

A case is reported of a 60 year-old patient with chronic disseminated intravascular coagulation (DIC) which was increased by the therapeutic embolization of a renal tumour. The patient had 2 primary carcinomas (renal and prostatic) with vertebral metastases, severe chronic anaemia (due to haematuria), and chronic DIC, with thrombocytopaenia, soluble complexes, and fibrinogen and fibrin degradation products. Therapeutic embolization of the renal artery was carried out with fragments of dura mater. Although the result was anatomically very satisfactory, the patient's condition worsened, with continuing haematuria, and development of an haematoma in the lumbar fossa. Coagulation factors and antithrombin III (AT III) concentrations decreased, whereas the activated partial thromboplastin, thrombin and reptilase times increased. The patient also suffered from acute renal failure (creatinine: 690 mumol.l-1). Treatment consisted in fluid replacement, red blood cell and platelet transfusions, 150 IU.kg-1.d-1 heparin and 20 IU.kg-1.d-1 AT III. Haematological tests returned to pre-embolization values on the ninth day. The sudden worsening in the patient's condition was probably due to the sudden massive release of tissue thromboplastins related to the renal necrosis induced by the therapeutic embolization. The use of heparin AT III in the management of this patient is discussed.
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PMID:[Worsening of chronic disseminated intravascular coagulation after embolization of the renal artery]. 233 Oct 88


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