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)

We studied the role of the fibrinolytic function in the invasiveness of murine melanoma B16F1 and F10 cells using a reconstituted matrix on a filter in a modified Boyden chamber. The main species of plasminogen activators (PAs) synthesized in cell lysates and released into conditioned media by these cells was found to be tissue-type PA (t-PA). The invasiveness of these cell lines was enhanced by adding plasminogen to the gel matrix. This enhancing effect of plasminogen was markedly suppressed by adding anti-t-PA IgG and plasmin inhibitors into the gel matrix, but less affected by anti-urokinase-type PA (u-PA) IgG, offering more evidence to the hypothesis that the activation of the fibrinolytic system by PAs plays an important role in the invasiveness of murine melanoma B16 cell lines, and indicating that t-PA contributed more than u-PA to the invasive potential of these cells into the pericellular matrix.
Invasion Metastasis 1992
PMID:Fibrinolysis activity promotes tumor invasiveness of B16 melanoma cell lines through a reconstituted gel matrix. 138 Sep 52

The study of the plasminogen-plasmin system has, in the past, contributed much to the understanding of fibrinolysis and thrombolysis. Attention is now focused on the role of the components of this system in many biologic functions. Findings of uPA, its receptor and its inhibitor in many tumor tissues and tumor cell lines, strongly implicate their involvement in tumor invasion, tumor cell proliferation and metastasis. The characteristics of the plasminogen activators, the uPA receptor and the plasminogen activator inhibitors as well as their expression and regulation in tumors and tumor cell lines are reviewed.
Cancer Metastasis Rev 1992 Nov
PMID:The plasminogen-plasmin system in malignancy. 142 20

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

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. Receptor-bound urokinase-type plasminogen activator (uPA) appears to play a key role in these events. uPA converts plasminogen into plasmin and thus mediates pericellular proteolysis during cell migration and tissue remodeling under physiological and pathophysiological conditions. uPA is secreted as an enzymatically inactive proenzyme (pro-uPA) by tumor cells and stroma cells. uPA exerts its proteolytic function on normal cells and tumor cells as an ectoenzyme after having bound to a high-affinity cell surface receptor. After binding, pro-uPA is activated by serine proteases (e.g. plasmin, trypsin or plasma kallikrein) and by the cysteine proteases cathepsin B or L, resp. Receptor-bound enzymatically active uPA converts plasminogen to plasmin which is bound to a different low-affinity receptor on tumor cells. Plasmin then degrades components of the tumor stroma (e.g. fibrin, fibronectin, proteoglycans, laminin) and may activate procollagenase type IV which degrades collagen type IV, a major part of the basement membrane. Hence receptor-bound uPA will promote plasminogen activation and thus the dissolution of the tumor matrix and the basement membrane which is a prerequisite for invasion and metastasis. Tissues of primary cancer and/or metastases of the breast, ovary, prostate, cervix uteri, bladder, lung and of the gastrointestinal tract contain elevated levels of uPA compared to benign tissues. In breast cancer uPA and PAI-1 antigen in tumor tissue extracts are independent prognostic factors for relapse-free and overall survival.
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PMID:Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. 151 91

The mechanism by which intravesical recombinant tissue plasminogen activator (rTPA) prevents tumor cell adherence to injured bladder surfaces, and the optimal parameters for the in vivo use of rTPA for adherence prevention, were evaluated. Intravesical rTPA decreased tumor cell adherence to sites of urothelial injury as a direct function of drug concentration in the intravesical fluid. Recombinant TPA concentrations of 1 mg/ml and 0.1 mg/ml significantly decreased tumor cell adherence relative to the control group. The efficacy of rTPA in removing adherent cells was time-dependent with maximal activity occurring at 15 min or later following intravesical administration. Intravesical rTPA effectively reduced the size of the tumor inoculum when administered either concomitant with, or subsequent to, tumor cell exposure. The relative efficacy of these two approaches was dependent upon the presence of serum in the intravesical fluid. Administration of rTPA concomitant with tumor cell exposure proved more effective in the absence of serum, while postadherence administration was more effective in the presence of 10% fetal calf serum. The addition of exogenous plasminogen to the rTPA solution did not increase anti-adherence activity relative to rTPA alone. However, blockade of endogenous plasminogen conversion with systemically administered epsilon-amino-caproic acid reversed the anti-adherence activity of exogenous rTPA. In vitro experiments evaluating cellular adherence to fibrin substrate confirmed that rTPA's anti-adherence activity was dependent on the presence of plasminogen. Exogenous rTPA administered immediately following tumor cell adherence decreased tumor cell implantation in animals receiving low to moderate tumor inoculums. These data suggest that rTPA prevents cellular adherence as a result of plasminogen activation and subsequent fibrinolysis. Intravesical rTPA administered in sufficient concentration for relatively short periods of time effectively reduces the adherent tumor inoculum and alters implantation as an inverse function of the tumor inoculum. This approach represents a novel strategy which may prove applicable for the prevention of implantation-mediated tumor recurrence at sites of surgical trauma.
Clin Exp Metastasis 1992 Mar
PMID:Intravesical recombinant tissue plasminogen activator for the prevention of implantation-mediated bladder tumor recurrence. 153 39

Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a solid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM produced in vitro and in basement membranes of the cornea and blood vessels in vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.
Cancer Metastasis Rev 1990 Nov
PMID:Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. 170 86

The correlation between the production of plasminogen activators (PA), especially urokinase-type PA (u-PA), by cancer cells and their metastatic potential was studied. For this purpose, cells from the human rectal adenocarcinoma tumor line (RCM-l/nu) originally maintained by serial passage in nude mice as the solid subcutaneous tumor, were injected into the spleen. Cancer cells from liver metastatic foci were suspended and then injected into the spleen. After 10 cycles of this selection, a highly metastatic liver tumor line termed L-10 was obtained. The amount of u-PA in the supernatant of the tumor homogenate of L-10 was larger than that of RCM-l/nu. Using an in vitro culture system, the media conditioned by L-10 cells had a higher PA activity and a higher u-PA antigen level than by RCM-l/nu cells. The apparent difference in u-PA activity and antigen levels of these two lines was not due to the difference in the production of plasminogen activator inhibitor (PAI), because PAI antigen level and PAI activity in the culture media were almost equal between them. No tissue-type PA production was detectable in these tumor lines. From these results we deduce that u-PA may play an important role in tumor metastasis.
Invasion Metastasis 1991
PMID:Correlation between urokinase-type plasminogen activator production and the metastatic ability of human rectal cancer cells. 176 31

The authors report on the influence of plasminogen activators (PA) on implantation of TA3Ha mammary tumor cells in the healing hepatic wounds of syngeneic strain A mice. Intravenously injected TA3Ha cells, although they rarely metastasize to the liver, formed tumors in the hepatic wounds of a significant percent (42%, P less than 0.0001) of mice. The frequency of tumor formation declined as the interval between surgery and tumor cell inoculation was increased. Furthermore, preexposure of cells to fibrinogen, fibronectin, laminin, or peptides containing the arginine-glycine-aspartic acid-serine residues dramatically reduced the frequency of tumor formation in the hepatic wounds. These results indicate that TA3Ha cells interact with fibrinogen-related proteins in the wound to aid their attachment and growth. Because these proteins are susceptible to digestion by plasmin, PA were used in this study to examine whether administration of these drugs to the mice would modulate tumor formation in the liver wounds. Among the PA tested, human plasmin B-chain-streptokinase complex (B-SK) and recombinant tissue plasminogen activator (t-PA) inhibited tumor implantation in a dose-related manner. Administration of 900 units (U) of B-SK or 3300 U of t-PA per mouse reduced the frequency of tumor formation from 42% to 0% (P = 0.02) and 11% (P = 0.02), respectively. The B-SK was complexed with p-nitrophenyl-p-guanidinobenzoate; it did not activate the plasminogen or inhibit tumor formation in the hepatic wounds. Although urokinase activated the plasminogen, it did not inhibit tumor implantation in the hepatic wound. Heparin, an anticoagulant that prevents conversion of fibrinogen to fibrin without being fibrinolytic, had no influence on tumor formation in the hepatic wounds. The PA can generate plasmin that digests the cell attachment proteins in wounds and consequently inhibits tumor cell attachment.
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PMID:Inhibition of tumor implantation at sites of trauma by plasminogen activators. 191 15

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

Implantation and subsequent placental development in many species including the human are dependent on trophoblast invasion of the uterine epithelium, the underlying basement membrane, connective tissue and blood vessels. However, trophoblast invasion in situ is strictly controlled by the microenvironment provided by the pregnant uterus. Key mechanisms underlying various steps in trophoblast invasion of basement membrane and stroma are similar to those identified in the case of invasive tumor cells: (a) attachment to basement membrane by binding to laminin and possibly other basement membrane components; (b) detachment from the basement membrane matrix prior to its penetration, a process that requires the presence of complex-type oligosaccharides on the cell surface; (c) breakdown of basement membrane components by trophoblast-derived metalloproteases (type IV and interstitial collagenase) and serine proteases (plasminogen activator). Type IV collagenase activity is stimulated by binding to laminin, a molecule also secreted by the trophoblast. Activation of trophoblast-derived metalloproteases appears to be plasmin-dependent. Plasmin results from the cleavage of plasminogen by trophoblast-derived plasminogen activator. Control of trophoblast invasion in situ is mediated by decidua-derived transforming growth factor beta (TGF beta) which in turn induces tissue inhibitor of metalloproteases (TIMP) both in the decidua and the trophoblast. We suggest that this control of trophoblast invasiveness is regulated both spatially as well as temporally during gestation. A preprogrammed decline in trophoblast invasiveness with increasing gestational age remains an additional possibility. The nature of the loss of control of trophoblast invasiveness in choriocarcinoma remains to be identified. Refractoriness to TGF beta action remains to strong possibility.
Cancer Metastasis Rev 1990 Dec
PMID:Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors. 209 85


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