fibrin and Neoplasm-Metastasis

Angiogenesis, the development of new blood vessels from existing vasculature, involves the migration, proliferation and differentiation of endothelial cells and is crucial for the growth and mestastasis of tumours. A specific association between cancer and the haemostatic system has long been recognised. Haemostatic mechanisms regulate blood flow by controlling platelet adhesion and fibrin deposition, and a number of haemostatic proteins have been shown to regulate angiogenesis, either directly, by interacting with endothelial cells themselves, or indirectly, by interacting with other regulators of angiogenesis. The polypeptide fibrinogen is the central protein in the haemostasis pathway and is found deposited in the majority of human and experimental animal tumours. In this review, the evidence for the ability of fibrinogen and various protein/peptide fragment derivatives to modulate angiogenic mechanisms in vitro and to affect tumour growth and metastasis in vivo is discussed.

Topics: Animals; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Peptide Fragments

Cancer patients are prone to venous thromboembolism (VTE), and this hypercoagulability favors tumor growth and metastasis. After a brief review of the clinical aspects of VTE and cancer, we discuss the pathogenesis of hypercoagulability with an emphasis on the role of tissue factor (TF). The discovery that, in addition to tumor cells, TF is expressed by tumor-associated macrophages and tumor-associated endothelial cells led to studies of the role of TF in the regulation of tumor angiogenesis. In human lung cancer, melanoma, and breast cancer, TF and vascular endothelial growth factor (VEGF) co-localize in tumor cells; a close correlation exists between TF and VEGF synthesis (P = .001) in tumor cell lines and with angiogenesis in vivo in a severe, combined immunodeficient mouse model. Transfection of a TF/VEGF low-producing human tumor cell line with full length TF complementary DNA (cDNA) results in conversion to a high producer of TF and VEGF; transfection of a deletion-mutant TF cDNA lacking cytoplasmic serine residues restores full TF procoagulant activity but not VEGF synthesis to the cells. These results suggest that the cytoplasmic tail of TF is necessary for tumor cell VEGF synthesis. Targeting of TF in tumors and tumor-associated blood vessels is discussed as a strategy for drug delivery and rational anti-cancer and anti-angiogenesis drug design.

Topics: Cell Division; Fibrin; Hemostatics; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Thromboplastin

There is considerable evidence that the hemostatic system is involved in the growth and spread of malignant disease. There is an increased incidence of thromboembolic disease in patients with cancers and hemostatic abnormalities are extremely common in such patients. Antihemostatic agents have been successfully used to treat a variety of experimental tumors, and several clinical trials in humans have been initiated. Although metastasis is undoubtedly multifactorial, intravascular coagulation activation and peritumor fibrin deposition seem to be important. The mechanisms by which hemostatic activation facilitates the malignant process remain to be completely elucidated. Of central importance may be the presence on malignant cells of tissue factor and urokinase receptor. Recent studies have suggested that these proteins, and others, may be involved at several stages of metastasis, including the key event of neovascularization. Tissue factor, the principal initiator of coagulation, may have additional roles, outside of fibrin formation, that are central to the biology of some solid tumors.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Biomarkers; Blood Coagulation Tests; Cell Adhesion; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Factor Xa; Fibrin; Fibrinolysis; Hemostasis; Heparin; Humans; Monocytes; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Platelet Activation; Platelet Aggregation Inhibitors; Receptors, Thrombin; Thrombophilia; Thrombophlebitis; Thromboplastin; Vitamin K

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Cysteine Endopeptidases; Fibrin; Fibrinogen; Humans; Microcirculation; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Thrombin

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.

Topics: Fibrin; Fibrinolysis; Humans; Neoplasm Metastasis; Neoplasms

Patients with cancer have an increased incidence of thromboembolic disease and haemostatic abnormalities, and there is considerable evidence that the haemostatic system is involved in the growth and spread of malignant disease. Anti-haemostatic agents have given promising results in the treatment of experimental tumours, and several clinical trials in humans have been initiated. The formation of fibrin around the tumour may be a particularly important factor in malignant dissemination. The precise mechanisms of peri-tumour fibrin deposition remain to be elucidated, but may involve alterations in local vascular permeability and the presence of tumour and/or macrophage procoagulants. In addition to their role in fibrin formation, haemostatic components may also be involved in neovascularisation and angiogenesis.

Topics: Blood Coagulation; Fibrin; Fibrinolysis; Hemostasis; Humans; Neoplasm Metastasis; Neoplasms; Thromboembolism

Topics: Animals; Anticoagulants; Blood Coagulation; Fibrin; Humans; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Platelet Aggregation Inhibitors

Abnormal hemostasis is a fundamental property of malignant disease, not merely an epiphenomenon attributable to therapy or to chronic illness. Many types of tumor cells express clotting initiators such as tissue factor and act again late in the coagulation pathway by providing a surface for prothrombinase generation. Thus, entry of tumor cells into the plasma, as during metastasis, may be expected to trigger intravascular clotting. However, and perhaps of greater importance, solid tumors growing outside of the blood vasculature regularly deposit fibrin locally in the tissues. They do so by rendering the microvasculature hyperpermeable, allowing fibrinogen and other plasma-clotting proteins to leak into the extravascular space where procoagulants associated with tumor cells or with benign stromal cells initiate clotting. Both fibrin deposition and turnover in solid tumors proceed at rapid rates. Thus, whether attributable to events in the intra- or extra-vascular space, the result is the same: abnormal clotting and fibrinolysis whose consequences may include protection from host inflammatory cells, modulation of the immune response, and induction of angiogenesis.

Topics: Blood Coagulation; Fibrin; Humans; Neoplasm Metastasis; Neoplasms; Thrombosis

Topics: Animals; Binding Sites; Cell Adhesion; Cell Membrane; Collagen; Cytoskeleton; Extracellular Matrix; Fibrin; Fibronectins; Genes; Heparin; Humans; Neoplasm Metastasis; Neoplasms; Receptors, Cell Surface; RNA Processing, Post-Transcriptional; Structure-Activity Relationship; Transcription, Genetic

Topics: Animals; Arteriosclerosis; Cell Adhesion; Cell Membrane; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Collagen; Endocytosis; Endothelium; Extracellular Matrix; Fibrin; Fibronectins; Growth Substances; Humans; Laminin; Lipid Bilayers; Lipoproteins; Lymphocytes; Membrane Proteins; Neoplasm Metastasis; Neoplasms; Oncogenes; Plasminogen Activators; Proteoglycans; Receptors, Cell Surface; Surface Properties

An association between cancer and the coagulation system was suggested by Trousseau more than a century ago and initial reports of fibrin deposition in the stroma of solid tumors date back some 25 years. However, the validity and generality of these observations have only quite recently been established, and their implications for an understanding of tumor biology, metastasis, and therapy are only now coming to be appreciated by investigators in the mainstream of cancer research. This article reviews the current status of fibrin's role in the biology of tumor growth, considering in turn: (1) the evidence that fibrin is present in tumors, the nature of such fibrin, and its relation to plasma fibronectin; (2) the mechanisms by which fibrin may come to be deposited in tumors; and (3) the potential biological and medical significance of tumor-associated fibrin deposition and degradation. Among the last are such important possibilities as a barrier function to the immune response and possible roles in angiogenesis, desmoplasia, and metastasis.

Topics: Animals; Blood Coagulation; Capillary Permeability; Cell Division; Cell Line; Fibrin; Humans; Immunity, Cellular; Lymph Nodes; Lymphocytes; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neovascularization, Pathologic

Most metastases in patients occur as a result of hematogenous dissemination of tumor cells. This process of metastasis is complex and consists of several steps, foremost of which is the arrest of circulating emboli in capillary beds and the formation of a thrombus at that site. Thrombus formation in the metastasis of human cancer was described first by Billroth in 1878. It was reported that the organization of tumor cell emboli, and the subsequent penetration of tumor cells into the capillary wall, was the first stage of metastasis. Since then, many investigations and observations have been made clinically as well as experimentally to clarify the process (or mechanisms) of tumor cell arrest and how to inhibit it. Coagulative and fibrinolytic pathways were believed to have a main role in thrombus formation. However, other factors responsible for the relationship between tumor cells and the host must be also considered. Elegant and extensive studies by Fidler and Kripke demonstrated that development of metastasis is not a random process, but a selection process of specialized subpopulations of highly metastatic cells within the primary tumors. Biochemical constituents and ionic properties on cell surfaces, deformability or locomotive activities of tumor cells, as well as thrombo-plastic-fibrinolytic activities, are also important factors determining the arrest patterns of circulating tumor cells. On the other hand, host defense factors against tumor cells in the bloodstream have been attracting much attention recently in tumor immunology. Host defense factors relating the arrest of tumor cells to the establishment of metastatic foci seemed difficult to define, since many studies showed contradictory data concerning the influence of immune response on tumor cell arrest. Hemodynamic abnormality may also influence the arrest of tumor cells in the circulation. Hypercoagulability induced from host tissues is greatly associated with the arrest patterns. Platelet activities might affect thrombus formation. Nevertheless, exact explanations of the process or mechanisms inhibiting or enhancing the arrest of tumor cells after hematogenous dissemination have not been obtained. In any event, for cancer treatment, it is important to determine which substances inhibit the arrest of circulating tumor cells and how to prevent hematogenous metastasis. In this review, we will focus upon coagulative and fibrinolytic processes and then upon substances that inhibit the arrest of

Topics: Animals; Anticoagulants; Blood Coagulation; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity, Cellular; Killer Cells, Natural; Melanoma; Mice; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Platelet Aggregation; Rats; T-Lymphocytes, Cytotoxic

Topics: Animals; Aspirin; Blood Vessels; Capillaries; Endothelium; Fibrin; Heparin; Lung Neoplasms; Microcirculation; Neoplasm Metastasis; Neoplasms; Platelet Aggregation; Warfarin

Topics: Animals; Blood Coagulation; Blood Platelets; Coumarins; Disease Models, Animal; Fibrin; Fibrinolysis; Hemostasis; Humans; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Platelet Aggregation; Warfarin

Topics: Animals; Anticoagulants; Antigens, Neoplasm; BCG Vaccine; Blood Coagulation; Cell Adhesion; Cell Line; Cell Survival; Endothelium; Fibrin; Fibrinolysis; Humans; Immunity; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Macrophages; Mycobacterium bovis; Necrosis; Neoplasm Metastasis; Neoplasms; Organ Specificity; Platelet Aggregation

It seems evident that fibrinogen and fibrin representing the final substrate und product of clotting system act as pathogenetic connecting links for development and spread of malignant tumors. The results reported demonstrate the influence of fibrin on the initial phase of haematogenic metastasis particularly. Several tumor-specific mechanisms are shown to cause frequently an accumulation of fibrin in malignant tumors. The results discussed here stress the importance of fibrin in tumors for tumor cells and tumor cell units. In the literature a large number of indications to fibrin depositions in experimental tumors is found, an attempt is made to compare these findings semiquantitatively. The last part of this article discusses the therapeutic and diagnostic consequences based on the possible key position of fibrin-(ogen) in the tumor pathology.

Topics: Animals; Anticoagulants; Blood Platelets; Fibrin; Fibrinogen; Fibrinolysin; Humans; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Urokinase-Type Plasminogen Activator

Topics: Blood Coagulation; Fibrin; Fibrinogen; Fibrinolysis; Hemorrhage; Heparin; Humans; Neoplasm Metastasis; Neoplasms; Thromboplastin; Thrombosis

Topics: Animals; Aorta; Autoradiography; Basement Membrane; Blood Vessels; Embolism; Endothelium; Fibrin; Fibrinolysis; HeLa Cells; Humans; Microscopy, Electron; Mitosis; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Plasminogen; Platelet Adhesiveness; Saphenous Vein; Thromboplastin; Thymidine; Tritium

Topics: Adult; Antineoplastic Agents; Blood Coagulation; Blood Coagulation Factors; Breast Neoplasms; Dextrans; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Rectal Neoplasms; Sulfates

Topics: Animals; Fibrin; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating

Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Contrast Media; Female; Ferric Compounds; Fibrin; Fibronectins; Humans; Hydrogen Peroxide; Magnetic Resonance Imaging; Manganese Compounds; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Metastasis; Oligopeptides; Signal-To-Noise Ratio; Transplantation, Heterologous

Secretion of PDI from platelets and endothelial cells is an important step of all thrombotic events. In the absence of extracellular PDI thrombus formation and fibrin generation may be impaired. Thrombin-mediated PDI secretion is regulated by the stimulation of P2Y

Topics: Androgen Receptor Antagonists; Blood Platelets; Blood Specimen Collection; Bodily Secretions; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Endothelial Cells; Endothelium; Female; Fibrin; Humans; Neoplasm Metastasis; Platelet Adhesiveness; Protein Disulfide-Isomerases; Purinergic P2Y Receptor Antagonists; Receptors, Androgen; Receptors, Purinergic P2Y12; Signal Transduction; Sulfhydryl Compounds; Thrombin; Thrombosis

The properties as biointerfaces of electroactive conducting polymer-peptide biocomposites formed by poly(3,4-ethylenedioxythiophene) (PEDOT) and CREKA or CR(NMe)EKA peptide sequences (where Glu has been replaced by N-methyl-Glu in the latter) have been compared. CREKA is a linear pentapeptide that recognizes clotted plasma proteins and selectively homes to tumors, while CR(NMe)EKA is an engineer to improve such properties by altering peptide-fibrin interactions. Differences between PEDOT-CREKA and PEDOT-CR(NMe)EKA reflect dissemblance in the organization of the peptides into the polymeric matrix. Both peptides affect fibrinogen thrombin-catalyzed polymerization causing the immediate formation of fibrin, whereas in the absence of thrombin this phenomenon is only observed for CR(NMe)EKA. Consistently, the fibrin-adsorption capacity is higher for PEDOT-CR(NMe)EKA than for PEDOT-CREKA, even though in both cases adsorbed fibrin exhibits round-like morphologies rather than the characteristic fibrous structure. PEDOT-peptide films coated with fibrin are selective in terms of cell adhesion, promoting the attachment of metastatic cells with respect to normal cells.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cell Adhesion; Coated Materials, Biocompatible; Female; Fibrin; Humans; Male; MCF-7 Cells; Membranes, Artificial; Neoplasm Metastasis; Oligopeptides; Polymers; Thiophenes; Thrombin

Clusters of circulating tumor cells (CTC) exhibit more robust metastatic properties than single CTC. Thus, understanding the distinct behaviors of CTC clusters and how CTC clustering is regulated may offer new insights into how to limit metastasis. In this study, we utilized an in vivo confocal system to observe the clustering behavior of CTC in real time, finding that the number of clusters increased proportionally with the growth of the primary tumor. Our experiments also indicated that the flow rate of the CTC clusters in blood vessels was relatively slower than single CTC due to increased vessel wall adhesion. Depending on disease stage, 5% to 10% of total CTC in circulation were in clusters, with this proportion increasing to >24% within lung metastases examined. Notably, in the 4T1 mouse model of breast cancer metastasis, we found that injecting host animals with urokinase-type plasminogen activator, a clinical thrombolytic agent, was effective at preventing the assembly of CTC clusters and prolonging overall host survival by approximately 20% relative to control animals. Our results suggest a tractable approach to limit metastasis by suppressing the formation or stability of CTC clusters circulating in the blood of cancer patients.

Topics: Animals; Cell Adhesion; Cell Line, Tumor; Disease Models, Animal; Female; Fibrin; Fibrinolytic Agents; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Neoplasm Metastasis; Neoplastic Cells, Circulating; Urokinase-Type Plasminogen Activator

Highly elevated microparticle (MP)-associated tissue factor (TF) activity was found in patients with pancreatic cancer, one of the most prothrombotic malignancies. It remains to be elucidated whether MP-TF activity reflects the prothrombotic state in these patients. MP-TF activity levels and the TF-dependent and -independent effect of MPs on fibrin clot formation were determined in patients with metastatic pancreatic cancer (n = 27), in healthy individuals (n = 10) and in plasma samples from lipopolysaccharide (LPS)-stimulated blood (LPS-plasma), which is rich in monocyte-derived TF-bearing MPs. The median MP-TF activity was 1.06 pg/mL (range, from 0.19 to 10.34 pg/mL) in patients with pancreatic cancer, 0.61 pg/mL (range, from 0.36 to 0.79 pg/mL) in LPS-plasma, and 0.18 pg/mL (range, from 0.04 to 0.39 pg/mL) in healthy individuals. MPs derived from LPS-plasma had the strongest impact on fibrin clot formation time (median, 157.6 seconds; range, from 149.5 to 170.4 seconds). Fibrin clot formation occurred significantly later in MPs derived from patients with pancreatic cancer (median, 273.4 seconds; range, from 146.6 to 354.4 seconds; P < 0.001) and in healthy individuals (median, 299.0 seconds; range, from 261.1 to 417.9 seconds; P < 0.001). Only in MPs derived from LPS-plasma the fibrin clot formation time dependent strongly on TF (median prolongation after TF blockade: 68% in LPS-plasma, 10% in patients with pancreatic cancer, and 4% in healthy individuals). In conclusion, highly elevated MP-TF activity was found in patients with metastatic pancreatic cancer, but TF-bearing MPs had a small effect on fibrin clot formation. TF-bearing MPs might not be the main mediators of the prothrombotic state associated with pancreatic cancer. However, the small but significant increase in coagulation potential by TF-bearing MPs might contribute to the multifactorial pathogenesis of venous thromboembolism in pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Fibrin; Humans; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Thromboplastin; Thrombosis

Topics: Adenocarcinoma; Female; Fibrin; Humans; Male; Neoplasm Metastasis; Pancreatic Neoplasms; Thromboplastin; Thrombosis

Tumour-repopulating cells (TRCs) are a self-renewing, tumorigenic subpopulation of cancer cells critical in cancer progression. However, the underlying mechanisms of how TRCs maintain their self-renewing capability remain elusive. Here we show that relatively undifferentiated melanoma TRCs exhibit plasticity in Cdc42-mediated mechanical stiffening, histone 3 lysine residue 9 (H3K9) methylation, Sox2 expression and self-renewal capability. In contrast to differentiated melanoma cells, TRCs have a low level of H3K9 methylation that is unresponsive to matrix stiffness or applied forces. Silencing H3K9 methyltransferase G9a or SUV39h1 elevates the self-renewal capability of differentiated melanoma cells in a Sox2-dependent manner. Mechanistically, H3K9 methylation at the Sox2 promoter region inhibits Sox2 expression that is essential in maintaining self-renewal and tumorigenicity of TRCs both in vitro and in vivo. Taken together, our data suggest that 3D soft-fibrin-matrix-mediated cell softening, H3K9 demethylation and Sox2 gene expression are essential in regulating TRC self-renewal.

Topics: Animals; Biosensing Techniques; Cell Line, Tumor; Cell Proliferation; Disease Progression; DNA Methylation; Female; Fibrin; Fluorescence Resonance Energy Transfer; Gene Silencing; Histone-Lysine N-Methyltransferase; Histones; Integrin beta1; Lysine; Melanoma; Melanoma, Experimental; Methylation; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Stem Cells; Promoter Regions, Genetic; RNA, Small Interfering; Skin Neoplasms; SOXB1 Transcription Factors; Time Factors

The progression of a tumor from benign to malign and localized to invasive and metastatic growth is the major cause of poor outcome of therapy in cancer patients. The deposition of fibrin along with other pro-coagulant molecules into the extracellular matrix obviously serves as a scaffold to support proliferation, migration and tumor cell growth as well as protection against the immune system. The use of antibodies as agents for the immunodetection of fibrin deposits in vivo has been hampered by anti-fibrin cross-reactivities with fibrinogen. For the immunohistochemical detection of fibrin we used highly specific monoclonal antibodies to a synthetic fibrinunique peptide, because the fibrin molecule shares many epitopes with fibrinogen. The monoclonal antibody was applied to adenocarcinoma of colon, mamma, pancreas, sarcoma and acute myeloic leukemia. In all tissue sections and cytospin preparations fibrin was identified in a direct apposition to the surface membranes of carcinoma and sarcoma cells, predominantly at the host-tumor interface and also in regions directly adjacent to zones of angiogenesis, whereas normal cells and tissue showed no deposits of fibrin. The findings will be supported by investigations that factors and components of the coagulation system could be detected in the tumor stroma and tumor cells. These factors are obviously produced and secreted by the malignant cells and deposited together with fibrinogen into the extracellular matrix. Our results show that basically all malignant cells examined, independently of ectodermal or mesenchymal derivation, themselves are the origin of hypercoagulability and fibrinolytic system inhibition.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Epitopes; Extracellular Matrix; Female; Fibrin; Fibrinogen; Fibrinolysis; Gene Expression Regulation, Neoplastic; Humans; Immune System; Immunohistochemistry; Male; Neoplasm Metastasis; Neoplasms; Peptides

The process of metastasis formation in cancer is not completely understood and is the main reason cancer therapies fail. Previously, we showed that dual liposomes simultaneously containing the hemostatic inhibitor, dipyridamole and the anticancer drug, perifosine potently inhibited metastasis, causing a 90% reduction in the number of lung metastases in a murine experimental metastasis model. To gain deeper insight into the mechanisms leading to the inhibition of metastasis by these dual liposomes, in the present study, the development of metastases by MT3 breast cancer cells in a mouse xenograft model was analyzed in more detail with regard to tumor cell settlement and metastatic growth. We found that the development of lung metastases by MT3 tumor cells is essentially dependent on the formation of fibrin clots as a precondition for the pulmonary arrest of tumor cells and the subsequent intravascular expansion of micrometastases before their invasion into the surrounding tissue.

Topics: Animals; Antineoplastic Agents; Blood Coagulation; Blood Vessels; Cell Line, Tumor; Dipyridamole; Female; Fibrin; Humans; Liposomes; Lung; Lung Neoplasms; Mammary Neoplasms, Experimental; Metallothionein 3; Mice; Mice, Nude; Neoplasm Metastasis; Phosphorylcholine; Platelet Aggregation Inhibitors; Xenograft Model Antitumor Assays

Circulating soluble fibrin (sFn) is elevated in many cancer patients. It is a marker for ongoing disseminated intravascular coagulation and may have prognostic significance. We have demonstrated that sFn inhibited monocyte adherence and cytotoxicity by a mechanism involving blockade of monocyte alphaMbeta2 and tumor cell CD54. It was, therefore, hypothesized that sFn also inhibits lymphocyte and interleukin-2-activated lymphocyte (LAK) adherence and cytotoxicity against tumor cells. This study sought to identify the lymphocyte subset responsible for adherence and killing of A375 melanoma cells and whether sFn inhibited these parameters. Lymphocyte and LAK cell adherence and cytotoxicity, which was adherence dependent, were inhibited by preincubation with purified or plasma-derived sFn. The lymphocyte and LAK cell activities were primarily a result of CD8(+) MHC (major histocompatibility complex) unrestricted cytotoxic T cells. These results suggest that elevated levels of circulating sFn may be immunosuppressive and may reduce the efficacy of adoptive immunotherapies.

Topics: Cell Adhesion; Cell Communication; Cells, Cultured; Cytotoxicity, Immunologic; Fibrin; Humans; Immune Tolerance; Immunotherapy, Adoptive; Killer Cells, Lymphokine-Activated; Lymphocytes; Neoplasm Metastasis

Multiple studies suggest that the hemostatic and innate immune systems functionally cooperate in establishing the fraction of tumor cells that successfully form metastases. In particular, platelets and fibrinogen have been shown to support metastatic potential through a mechanism coupled to natural killer (NK) cell function. As the transglutaminase that ultimately stabilizes platelet/fibrin thrombi through the covalent crosslinking of fibrin, factor (F) XIII is another thrombin substrate that is likely to support hematogenous metastasis.. Directly define the role of FXIII in tumor growth, tumor stroma formation, and metastasis.. Tumor growth and metastatic potential were quantitatively and qualitatively evaluated in wild-type mice and gene-targeted mice lacking the catalytic FXIII-A subunit.. Loss of FXIIIa function significantly diminished hematogenous metastatic potential in both experimental and spontaneous metastasis assays in immunocompetent mice. However, FXIII was not required for the growth of established tumors or tumor stroma formation. Rather, detailed analyses of the early fate of circulating tumor cells revealed that FXIII supports the early survival of micrometastases by a mechanism linked to NK cell function.. Factor XIII is a significant determinant of metastatic potential and supports metastasis by impeding NK cell-mediated clearance of tumor cells. Given that these findings parallel previous observations in fibrinogen-deficient mice, an attractive hypothesis is that FXIII-mediated stabilization of fibrin/platelet thrombi associated with newly formed micrometastases increases the fraction of tumor cells capable of evading NK cell-mediated lysis.

Topics: Animals; Blood Platelets; Factor XIII; Fibrin; Killer Cells, Natural; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Thrombosis; Transglutaminases; Tumor Escape

Tumor cell-associated tissue factor (TF) is a powerful determinant of metastatic potential. TF may increase metastasis by supporting thrombin-mediated proteolysis, through intracellular signaling events mediated by the TF cytoplasmic domain, through TF/fVIIa/fXa-mediated activation of protease-activated receptors, or through a combination of these processes. To better define the relationship between tumor cell-associated TF and circulating hemostatic factors in malignancy, we generated a set of C57Bl/6-derived tumor lines genetically lacking TF, expressing wild-type murine TF, or expressing a mutant TF lacking the cytoplasmic domain. Comparison of the metastatic potential of these cells in immunocompetent mice with genetic deficits in prothrombin, platelet function, or fibrinogen revealed that TF supports metastasis through mechanisms independent of the cytoplasmic domain, but dependent on each of these distal hemostatic factors. TF was neither required for primary tumor growth nor necessary for initial localization of embolized tumor cells within the lungs. Rather, tumor cell fate studies indicated TF supports metastasis by increasing the survival of micrometastases. One mechanism linking TF to metastasis is through a fibrin(ogen)-dependent and platelet-dependent restriction in natural killer cell-mediated clearance of micrometastases. However, TF also supported the early success of micrometastases through an additional mechanism independent of natural killer cells, but coupled to circulating prothrombin.

Topics: Animals; Blood Coagulation Factors; Blood Platelets; Cell Line, Tumor; Fibrin; Killer Cells, Natural; Mice; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prothrombin; Thromboplastin

We have shown that the thrombin G-protein coupled receptors (GPCR) designated as protease-activated receptors (PAR-1) are expressed in primary cancer cells isolated from peritoneal and pleural malignant effusions. Here, our main goal was to evaluate several coagulation and thrombin activation effectors and markers in a series of 136 malignant effusions from cancer patients with gastrointestinal, lung and mammary carcinomas. All these patients present a highly activated coagulation system in blood and their malignant effusions, as indicated by high levels of prothrombin F1.2 fragments and D-dimers. Notably, we detected in the effusions all the coagulation factors of the tissue factor pathway inducing thrombin activation, namely factors VII, V, X and II, as well as high VEGF levels and IGF-II in mature and precursor forms. Fibrin clot formation also correlated with higher levels of free ionized calcium (iCa), suggesting that iCa and its binding protein albumin are regulatory factors for fibrinogenesis in effusions. Consequently, thrombin, VEGF and IGFII appear to converge in the promotion of survival and invasivity of the metastatic cancer cells from blood to the malignant effusions. Thus, we add new insights on the interconnections between blood coagulation disorders in cancer patients and thrombin activation in malignant effusions, including their functional interaction with PAR in metastatic cancer cells. Based on these data we propose to counteract the metastatic cascades by targeted invalidation of key effectors of the coagulation system. Therefore, potential therapeutic approaches include the application of thrombin protease inhibitors, VEGF-blocking antibodies, and drugs targeting the VEGF and thrombin signaling pathways, such as tyrosine kinase or GPCR inhibitors.

Topics: Aged; Antineoplastic Agents; Antithrombins; Ascitic Fluid; Blood Coagulation; Blood Coagulation Factors; Breast Neoplasms; Calcium; Case-Control Studies; Factor V; Factor VII; Factor X; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Gastrointestinal Neoplasms; Humans; Insulin-Like Growth Factor II; Lung Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Peptide Fragments; Pericardial Effusion; Pleural Effusion, Malignant; Proteins; Prothrombin; Serum Albumin; Thrombin; Thromboplastin; Vascular Endothelial Growth Factor A

To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking Galphaq, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. Analyses of the distribution of radiolabeled tumor cells demonstrated that platelet function, like fibrinogen, significantly improved the survival of circulating tumor cells in the pulmonary vasculature. More detailed studies showed that the increase in metastatic success conferred by either platelets or fibrinogen was linked to natural killer cell function. Specifically, the pronounced reduction in tumor cell survival observed in fibrinogen- and Galphaq-deficient mice relative to control animals was eliminated by the immunologic or genetic depletion of natural killer cells. These studies establish an important link between hemostatic factors and innate immunity and indicate that one mechanism by which the platelet-fibrin(ogen) axis contributes to metastatic potential is by impeding natural killer cell elimination of tumor cells.

Topics: Animals; Blood Platelets; Cell Survival; Fibrin; Fibrinogen; GTP-Binding Protein alpha Subunits, Gq-G11; Killer Cells, Natural; Lung; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasms; Platelet Activation; Thrombosis

Vascular endothelial growth factor (VEGF)-induced vascular permeability (VP) is a hallmark of tumor growth and metastasis. Previous studies have shown a requirement for Src kinase in VEGF-mediated VP and signaling in blood vessels. In this study, we have examined the effect of Src-mediated reduced VP on tumor growth and metastasis. The growth and spontaneous metastasis of VEGF-expressing tumor cells were determined in Src-knockout (src(-/-)) or control mice (src(+/+) or src(+/-)). In comparison to control mice, src-null mice had a significant reduction in tumor-induced VP as well as a subsequent reduction in spontaneous metastasis. In contrast, primary tumor weight and vascular density were unchanged between src-null and control mice. Consistent with a role for Src in the extravasation of tumor cells from the circulation, direct intravenous injection of lung carcinoma cells resulted in a more than 2-fold reduction in lung tumor burden in src-null mice compared to control mice. The comparison of the results from the experimental metastasis and the spontaneous metastasis models suggests that there are defects in VP in the primary site of Src-deficient mice and that there may be an essential role for Src and Src-mediated VP in tumor metastasis to the lung.

Topics: Animals; Capillary Permeability; Carcinoma, Lewis Lung; Cell Line, Tumor; Cell Proliferation; Fibrin; Fibrin Fibrinogen Degradation Products; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Metastasis; Neovascularization, Pathologic; src-Family Kinases; Vascular Endothelial Growth Factor A

Topics: Blood Coagulation Disorders; Breast Neoplasms; Cell Hypoxia; Female; Fibrin; Fibrinogen; Humans; Middle Aged; Neoplasm Metastasis

Detailed studies tumor cell-associated procoagulants and fibrinolytic factors have strongly suggested that local thrombin and plasmin generation may be important in tumor progression. Given that one target for both these serine proteases is fibrinogen, a logical extension of this hypothesis is that local fibrin deposition and dissolution may be key determinants of tumor growth and/or dissemination. To directly test this concept, we initiated studies of tumor growth, experimental metastasis, and spontaneous metastasis in C57Bl/6-inbred mice with and without fibrinogen. Using two established C57Bl/6-derived tumor cell lines, Lewis lung carcinoma and B16-BL6 melanoma, fibrinogen deficiency was found to strongly diminish, but not prevent, the development of lung metastases in both experimental and spontaneous metastasis assays. This difference was not a consequence of any obvious difference in tumor stroma formation or the growth of primary or secondary tumors. Rather, tumor cell fate studies argued that there is an important role of fibrin(ogen) in the sustained adhesion and/or survival of tumor cell emboli within the lung. The specific thrombin inhibitor, hirudin, was also shown to strongly diminish metastatic potential, consistent with earlier reports. More importantly, hirudin was found to further diminish the already low metastatic potential of tumor cells in fibrinogen-deficient mice. We conclude that fibrin(ogen) is a critical determinant of metastatic potential, but thrombin appears to contribute to tumor cell dissemination through at least one fibrinogen-independent mechanism. Further, these findings suggest that therapeutic strategies directed at several hemostatic factors might be useful in the suppression of metastatic disease.

Topics: Animals; Blood Platelets; Fibrin; Fibrinogen; Mice; Mice, Inbred C57BL; Neoplasm Metastasis

Topics: Animals; Fibrin; Fibrinogen; Hemostasis; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating

The glycosaminoglycan hyaluronan, which supports tumor cell migration and metastasis, interferes with fibrin polymerization and leads to increased fiber size and porosity of fibrin clots. Here we have studied the proportionate effect of fibrin polymerization on hyaluronan-mediated migration of glioblastoma cells. The structural and physical properties of hyaluronan-containing fibrin gels were analyzed by turbidity measurement, laser scanning microscopy, compaction assay, and calculation of pore size by liquid permeation. When fibrin polymerized in the presence of hyaluronan or dextran, the resulting gels strongly stimulated cell migration, and migration significantly correlated with fiber mass-to-length ratios and pore diameters. In contrast, cell migration was not induced by addition of hyaluronan to supernatants of already polymerized gels. Hyaluronan-mediated migration was inhibited in fibrin gels by antibodies to alphav- and beta1integrins and the disintegrin echistatin, but not by antibodies to the hyaluronan receptor CD44 (up to 50 microg/ml). As a control, we show that anti-CD44 (10 microg/ml) inhibited cell migration on a pure hyaluronan matrix using a two-dimensional Boyden chamber system. In contrast to three-dimensional migration, the migration of cells on the surfaces of variably structured fibrin gels was not significantly different, indicating that increased gel permeability (porosity) may account for hyaluronan-mediated migration. We conclude that, in complex three-dimensional substrates, the predominant effect of hyaluronan on cell migration might be indirect and requires modulation of fibrin polymerization.

Topics: Animals; Antigens, CD; Biopolymers; Cell Movement; Dextrans; Fibrin; Gels; Glioblastoma; Humans; Hyaluronan Receptors; Hyaluronic Acid; Integrin alphaV; Integrin beta1; Intercellular Adhesion Molecule-1; Neoplasm Invasiveness; Neoplasm Metastasis; Tumor Cells, Cultured

Considerable evidence exists linking hemostasis and malignancy. Platelet adhesion to tumor cells has been implicated in the metastatic process. Plasma fibrinogen (Fg) and fibrin (Fn) monomer, increased in cancer, may play a role in tumor biology. Binding of Fn monomer to tumor cells and its effect on platelet-tumor cell adhesion in a flowing system were studied. Fn monomer was produced by adding thrombin (1 micro/mL) to FXIII- and plasminogen-free Fg in the presence of Gly-Pro-Arg-Pro (GPRP) amide. Fn monomer binding to live A375 cells was visualized by confocal laser scanning microscopy (CLSM). Adherent cells were perfused for 1h with Fn monomer, washed and stained in situ with anti-human Fn (American Biogenetic Sciences, Inc.) followed by goat anti-mouse IgG(FITC). Platelet adherence to Fn monomer treated A375 cells was performed under flow conditions by passing platelets (5x10(4)/microl 0.25 mL/min; labeled with the carbocyanine dye DiI) over the tumor cells for 30 min. CLSM images were obtained after washing. There was considerable binding of Fn monomer, but not Fg alone. Platelets adhered relatively weakly to untreated A375 cells and this was not significantly affected by pre-treatment of the tumor cells with fibrinogen or thrombin. However, pre-treatment with Fn monomer resulted in extensive platelet binding to tumor cells, suggesting that coagulation activation and the subsequent increase in circulating Fn monomer may enhance platelet adhesion to circulating tumor cells and thereby facilitate metastatic spread.

Topics: Blood Platelets; Fibrin; Humans; Neoplasm Metastasis; Neoplasms; Platelet Adhesiveness; Tumor Cells, Cultured

This investigation was carried out to evaluate fibrin formation and degradation in various types of solid neoplasms by measuring fibrinopeptide A (fpA) in the plasma with a radioimmunoassay and D-dimer (DD) with an enzyme-linked immunosorbent assay in 176 cancer patients; 77 of them showed signs of distant metastasis (M1). FpA and DD were abnormally elevated in 81 and 143 patients respectively. FpA and DD were significantly correlated and unrelated to plasma fibrinogen. Both fpA and DD levels were more elevated in M1 than M0 patients. Coumarin anticoagulants, administered to 32 patients of our series with the aim of preventing cancer growth and dissemination, caused a significant decrease both in fpA and DD levels. Our data provide evidence of increased in vivo fibrin formation and degradation in solid neoplasms: oral anticoagulants can modulate cancer-related hypercoagulation.

Topics: Adult; Aged; Aged, 80 and over; Coumarins; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Fibrinopeptide A; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Radioimmunoassay

Topics: Animals; Fibrin; Humans; Immune Tolerance; Immunologic Surveillance; Macrophages; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental

This study was undertaken to determine if primary breast tumor plasminogen activator expression correlates with skeletal metastasis in breast cancer. Total plasminogen activator activity was significantly lower in tumors of patients with recurrence than in recurrence-free patients. Similarly, the primary tumors of patients with skeletal metastasis contained considerably less enzyme activity compared with those of patients surviving without skeletal metastasis. When patients with skeletal metastasis were categorized in terms of their recurrence pattern, those who had skeletal metastasis without other organ metastasis had significantly less tissue-type plasminogen activator antigen in their primary breast tumors than did those who had metastasis to other organs. Furthermore, a significantly lower level of tissue-type plasminogen activator antigen was found in primary tumors associated with axial bone metastasis than in those associated with appendicular bone metastasis. These results suggest that tissue-type plasminogen activator is involved in skeletal metastasis formation by its effects through the vertebral venous plexus.

Topics: Bone Neoplasms; Breast Neoplasms; Fibrin; Fibrinolysis; Humans; Neoplasm Metastasis; Neoplasm Proteins; Neoplastic Cells, Circulating; Spinal Neoplasms; Spine; Tissue Plasminogen Activator; Veins

Activation of blood coagulation and local fibrin deposition may contribute to tumor metastasis. We have examined the ability of four human tumor cell lines (COLO 205, HepG2, J82 and CAPAN-2) to augment the conversion of prothrombin to thrombin by factor Xa and calcium in the presence and absence of exogenous factor Va. Using a chromogenic substrate assay to assess thrombin formation, we observed that all the above cell lines accelerated prothrombin activation in the absence of exogenous factor Va. The order of effectiveness was COLO 205 greater than HepG2 greater than J82 greater than CAPAN-2. In the absence of cells, no detectable thrombin formation occurred. Pretreatment of COLO 205 and HepG2 cells with anti-human factor V IgG inhibited prothrombin activation in a dose-dependent manner, but was without effect in J82 and CAPAN-2 incubation mixtures. Factor V coagulant activity was observed in COLO 205 and HepG2 cells as well as their culture media, but was not detected in J82 and CAPAN-2 cells or their culture media. Biosynthetic labeling and immunoprecipitation studies revealed that COLO 205 and HepG2 cells constitutively synthesized factor V or a factor-V-like molecule that comigrated with human factor V/Va on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. All four tumor cell lines exhibited saturation binding of exogenous human factor Va resulting in a dose-dependent enhancement of their ability to augment prothrombin activation. Our results indicate that these tumor cells can readily assemble a functional cell surface prothrombinase complex that may be important in fibrin deposition associated with the growth and metastatic progression of these, and perhaps, other tumors.

Topics: Enzyme Activation; Factor V; Factor Xa; Fibrin; Humans; Membrane Proteins; Neoplasm Metastasis; Neoplasm Proteins; Prothrombin; Thrombin; Thromboplastin; Tumor Cells, Cultured

In order to characterize further the previously observed induction of a highly metastatic phenotype in mouse bladder carcinoma cells by Ha-ras transfection, we studied production of plasminogen activator, in vitro invasiveness, and the potential for lung colonization of these cells. The parent carcinoma cells produced predominantly tissue-type plasminogen activator. Out of 13 clones of ras-transfected cells tested, 8 secreted quantitatively elevated levels of plasminogen activator (up to 3.5-fold) as compared to the control transfectants. The plasminogen activator activity in cell lysates was maximally increased 3-fold, the surface-associated activity increased 2.5-fold. The secreted plasminogen activator of cloned ras-transfected cells was characterized to be predominantly of the urokinase type (71.3% compared to 20.5% with the parental BL cells). Thus, in addition to the quantitative augmentation of plasminogen activator production and secretion in a large fraction of the ras-transfected cell population, a significant qualitative shift from tissue-type to urokinase-type has been observed. In addition, ras-transfection augmented the capacity of the cells for invasion into Matrigel in a double-filter in vitro assay as well as their ability to colonize the lungs of syngeneic animals. These malignant properties of the transfected cells might be responsible for their highly metastatic behaviour induced by ras transfection.

Topics: Animals; Fibrin; Genes, ras; Humans; Lung Neoplasms; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Phenotype; Transfection; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Urokinase-Type Plasminogen Activator

Coumarins inhibit metastasis in a number of animal models, but the mechanism of this effect remains unclear. We have investigated the relationship between the coagulation system and metastasis using a new model system, involving i.v. injection of Mtln3 rat mammary carcinoma cells into Fischer 344 rats, and subsequent estimation of pulmonary seeding. Injection of factors II, VII, IX and X elevated the median number of surface pulmonary seedlings per animal to 182, and injection of factors II, IX and X to 181, compared with a median for control animals of 12 (P less than 0.001). Injection of factor VII alone, or of bovine serum albumin did not significantly affect pulmonary seeding. In a second experiment, arvin defibrination reduced the mean plasma fibrinogen concentration to 76.8 mg dl-1 from a control value of 228 mg dl-1. This degree of defibrination had no significant effects on pulmonary seeding, nor on the enhancing effects of factor complex injection (median numbers of seedlings per animal; control 15, arvin 21, arvin plus factors II, VII, IX and X 170, factors II, VII, IX and X only, 157). Factor complex injections did not detectably shorten thrombotest clotting times. In vitro testing suggested that Mtln3 cells contain little or no conventional factor X activating cancer procoagulant. The complex of coagulation factors II, IX and X appears to contain a component which greatly enhances metastasis in this model. This may explain the previously reported antimetastatic effect of coumarin anticoagulants, which suppress factors II, VII, IX and X. The enhancing effect of the factor complex does not appear to be altered by significant reductions in fibrin forming capacity, and defibrination itself has no effect on metastasis. These findings suggest the possibility that the effect of this factor complex on metastasis may be mediated via mechanisms other than the formation of a fibrin clot.

Topics: Ancrod; Animals; Anticoagulants; Blood Coagulation Factors; Female; Fibrin; Fibrinogen; Lung Neoplasms; Mammary Neoplasms, Experimental; Neoplasm Metastasis; Rats; Rats, Inbred F344; Tumor Cells, Cultured

Topics: Adult; Aged; Carcinoma; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Middle Aged; Neoplasm Metastasis; Plasminogen; Prognosis; Protease Inhibitors; Stomach Neoplasms

When Lewis lung carcinoma with low thromboplastic and low fibrinolytic activities was implanted subcutaneously to mice, administration of tranexamic acid inhibited metastasis formation in the lungs. This effect was considered to be mediated by prevention of cell release from the implanted sites. Fibrin formation around tumor cells in the vessels of primary foci was observed in the mice given tranexamic acid. On the other hand, urokinase significantly enhanced pulmonary metastases and many free tumor cells were observed intravascularly in primary foci of the mice given urokinase.

Topics: Animals; Cyclohexanecarboxylic Acids; Female; Fibrin; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Rabbits; Tranexamic Acid; Urokinase-Type Plasminogen Activator

As shown in earlier studies the formation of metastases after i.v. tumor cell injection in rats is increased in the immediate post-traumatic period and treatment with heparin, thrombocytopenia, and defibrinogenation decreases the formation of metastases. Thrombocytopenia also inhibits the stimulating effect of trauma on metastasis formation. The results of the studies reported in this paper show that the changes of metastasis formation induced by the factors mentioned above with few exceptions are well correlated to the lodgement of the injected tumor cells. Thus, heparin treatment and thrombocytopenia decrease the pulmonary lodgement of i.v. injected tumor cells. Trauma increases the pulmonary lodgement of i.v. injected tumor cells but when trauma is combined with thrombocytopenia, the effect of thrombocytopenia dominates and the pulmonary lodgement of tumor cells decreases when compared to control conditions. Despite this, trauma still gives rise to increased tumor cell lodgement during thrombocytopenia.

Topics: Adenosine Diphosphate; Animals; Fibrin; Heparin; Lung Neoplasms; Neoplasm Metastasis; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation; Rats; Thrombocytopenia; Wounds and Injuries

Blood fibrin being deposited around the circulating tumor cells seems to contribute to metastatic spread, thus enhancing the cell implantation. Whereas the same fibrin hampers cells detachment from a tumor node and their further dissemination in the organism. The anticoagulation blood system interfers with the fibrin formation, whereby inhibiting the cell implantation and metastatic spread, but is may also enhance them, contributing to detachment and dissemination of tumor cells. In this respect, to enhance the antimetastatic resistance of the body there must be a balanced interaction between the coagulation and anticoagulation blood systems with an unremoved tumor and the increased anticoagulation function after the tumor node resection especially in the early postoperative period.

Topics: Animals; Blood Coagulation; Fibrin; Fibrinolysis; Hemostasis; Neoplasm Metastasis; Neoplasms, Experimental; Rats

Topics: Animals; Batroxobin; Fibrin; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Experimental; Peptide Hydrolases; Time Factors

The results of this study suggest that many malignant tumors contain low levels of fibrinolytic activator activity. Evidence is presented to suggest that this low activity may be due to the presence of an inhibitor of fibrinolysis. The presence or absence of measurable fibrinolytic activator activity, and/or inhibitor in neoplastic growths may enable one to predict the probability of viable metastases to a distant site.

Topics: Anticoagulants; Blood Platelets; Fibrin; Fibrinolysis; Humans; Neoplasm Metastasis; Neoplasms

Effect of urokinase on the tumor growth and metastasis formation of rabbit V2 carcinoma, having low thromboplastic and high fibrinolytic activities, was examined. Weight of the tumor and lymphogenous metastases tended to increase, but the number of metastatic foci in the lungs was unchanged by the administration of urokinase. Diminution of fibrin deposits and connective tissue reaction in association with increase in the pattern of invasive growth was recognized at the advancing border of the tumors in the urokinase-treated group. In the intravenously induced pulmonary metastases, the number of metastatic foci decreased significantly in the urokinase-treated group. Fibrin was demonstrated at the site of tumor cell embolism by the conjugated anti-rabbit fibrinogen antibody. The growth of metastatic foci in the lungs was not affected by the treatment with urokinase. Enhancing effect of urokinase on fibrin resolution might promote the local tumor growth and release of tumor cells into the vessels, but interfere with the lodgement of tumor cells in remote organs.

Topics: Animals; Endopeptidases; Fibrin; Fibrinolysis; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Experimental; Rabbits; Urokinase-Type Plasminogen Activator

Topics: Animals; Fibrin; Liver Neoplasms, Experimental; Neoplasm Metastasis; Rats

A technique using computerized data handling for following the fate of 125I-fibrinogen through various physiological compartments is presented. Its use in detecting fibrin build up in patients with metastatic tumors and cancer-caused DIC is explained. An increase in j3u (fractional catabolic rate as seen in the urine data) throughout the course of a study was found to be an important indicator of extravascular fibrin build up.

Topics: Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Humans; Mathematics; Neoplasm Metastasis; Neoplasms

In the last few years increased release of fibrinolytic enzymes from malignant cells has been observed, but the significance of this property in relation to malignant growth is still not fully understood. Antifibrinolytic drugs decrease the growth rate of some experimental tumours and might have a similar effect on human malignant tumours. Antifibrinolytic drugs might also decrease the intravascular shedding of tumour cells from primary tumours, but might on the other hand enhance the lodgement of those metastatic tumour cells already in the vascular bed of recipient organs.

Topics: Animals; Antifibrinolytic Agents; Fibrin; Fibrinolysis; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Plasminogen Activators

Topics: Carcinoma, Bronchogenic; Diagnosis, Differential; Fibrin; Humans; Lung Neoplasms; Lymphoma; Mesothelioma; Neoplasm Metastasis; Pleural Diseases; Pleural Neoplasms; Radiography

The association of fibrin and tumour cells on a sclerosed mitral valve in a 62-year-old woman is described. This was the first indication of malignant disease but bilateral ovarian cancer was proved two months later. ino further tumour deposits have been found in fifteen months. The tumour deposit on the valve was most likely a metastasis but primary heart valve sarcoma has not been positively excluded. If the lesion was a secondary deposit this has possible implications for the role of fibrin in metastasis in humans.

Topics: Female; Fibrin; Heart Neoplasms; Heart Valve Diseases; Humans; Middle Aged; Mitral Valve; Neoplasm Metastasis; Neoplastic Cells, Circulating; Ovarian Neoplasms; Ovary; Sarcoma; Sclerosis

Topics: Arginine; Blood Coagulation Disorders; Fibrin; Humans; Neoplasm Metastasis; Neoplasms; Thrombosis

Tumor emboli were produced in lungs of Sprague-Dawley rats by i.v. injection of Walker 256 tumor cells into the tail vein. Tissues were examined by electron microscopy at periods from 30 sec to 72 hr after tumor injection. Two methods of conventional staining were used, in addition to immunoperoxidase techniques, with antifibrin antibodies produced in rabbits. Tumor cells accompanied by a platelet mass were seen in pulmonary arterioles at the earliest time period (30 sec). By conventional staining, small amounts of fibrin were detected within the platelet clumps by 5 min after inoculation. Periodicity indicating stable fibrin was not seen by this technique until 15 to 45 min. When peroxidase-labeled antibody was applied to tissue, sections showed fibrin-positive material at 30 sec, and periodicity of fibrin was detected by 5 min. Fibrin reached a maximum by both techniques at about 1 hr and disappeared, along with the platelets, at about 9 hr. When fibrinolysin was injected prior to the tumor cell inoculation, platelets and fibrin were either absent or present only in traces, and no stable fibrin was detected. These observations show that fibrin occurs very early in small amounts in association with tumor cell emboli, and is removed while the cells are still intravascular.

Topics: Animals; Blood Platelets; Carcinoma 256, Walker; Fibrin; Lung Neoplasms; Neoplasm Metastasis; Platelet Aggregation; Rats; Time Factors

Topics: Adolescent; Age Factors; Blood Coagulation Tests; Blood Platelet Disorders; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Fibrin; Fibrinogen; Humans; Kidney Neoplasms; Lymphatic Diseases; Lymphoma; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Osteosarcoma; Retinoblastoma; Rhabdomyosarcoma; Sarcoma, Ewing; Wilms Tumor

Topics: Aged; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Dysgerminoma; Female; Fibrin; Humans; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Prostatic Neoplasms; Stomach Neoplasms; Testicular Neoplasms; Thrombophlebitis

Experiments were undertaken to test a new hypothesis for the mechanism underlying the Révész effect. The hypothesis proposes that lethally irradiated (LI) tumour cells enhance the take probability of a small number of transplanted viable (V) tumour cells mixed with them by exerting a thromboplastic effect at the site of injection; local fibrin formation prevents emigration of V cells from the site or secures their survival there. The evidence presented to support this hypothesis is as follows: in the case of 3 isogeneically transplanted tumours, admixed particulate brain extract simulated the effect of LI cells in increasing the take probability of V cells; brain extract simulated the effect of LI cells in greatly delaying the disappearance of (125)IUdR-labelled viable carcinoma cells from the injection site; V cells acquired a raised take probability by their incorporation in fibrin clots; it was confirmed that admixed erythrocytes increased the take probability of V cells; using a newly devised microscopical test for detection of the thromboplastic activity of individual cells, it was found that cell death was almost always required for the display of such activity; lymphocytes and bone marrow cells, ineffective in enhancing the take of V cells, were almost totally devoid of thromboplastic activity. Possible explanations are given for failure of a fibrinogen depleting agent, ancrod (Arvin) to inhibit the Révész effect when administered to recipients. It is concluded that the evidence strongly supports the hypothesis presented whilst seriously weakening the long-standing theories that admixed LI cells act by provision of nutrients or by local quenching of postulated immune reactivity.

Topics: Animals; Brain; Cell Line; Cell Survival; Fibrin; Leukemia, Experimental; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Peptide Hydrolases; Radiation Effects; Thromboplastin; Tissue Extracts; Venoms

Topics: Adult; Ascitic Fluid; Female; Fibrin; Fibrinogen; Humans; Neoplasm Metastasis; Ovarian Neoplasms; Sertoli-Leydig Cell Tumor

Topics: Aged; Blood Coagulation Tests; Blood Platelet Disorders; Chronic Disease; Disseminated Intravascular Coagulation; Fibrin; Gastrointestinal Hemorrhage; Heparin; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Prothrombin Time; Thromboplastin

Topics: Fibrin; Fibrinogen; Hematuria; Humans; Kidney Neoplasms; Neoplasm Metastasis; Nephrectomy; Prognosis

Topics: Afibrinogenemia; Animals; Blood Cell Count; Blood Platelets; Female; Fibrin; Fibrinogen; Kidney; Liver; Lung; Male; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Rabbits; Snakes; Venoms

Topics: Aged; Anemia, Hemolytic; Disseminated Intravascular Coagulation; Female; Fibrin; Heparin; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Thrombocytopenia

Topics: Aminocaproates; Blood Coagulation; Breast Neoplasms; Colonic Neoplasms; Female; Fibrin; Fibrinogen; Fibrinolysis; Gastrointestinal Neoplasms; Humans; Immunoelectrophoresis; Intestinal Neoplasms; Kidney Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Prostatic Neoplasms; Rectal Neoplasms; Thrombin; Urinary Bladder Neoplasms; Urogenital Neoplasms

After the intravenous injection of Walker 256 tumour cells into rats the platelet count decreased rapidly and remained low during the following period of observation. The platelet decrease was closely related to the number of cells injected. Intra-arterial tumour cell injections required a considerably higher tumour cell count to produce a comparable thrombocytopenia. Non-viable tumour cells and tumour cell fragments induced a similar decrease of circulating platelets. Neither viable tumour cells nor tumour cell fragments aggregated rat platelets in vitro. The presence of fibrin monomers in tumour cell injected animals suggested intravascular fibrin deposition; the plasma fibrinogen level, however, did not decrease significantly. Isotope studies using (51)Cr labelled platelets revealed a rapid disappearance of the platelets from the circulation and their trapping in the lung-the primary site of tumour cell lodgement. Dipyridamole and ancrod pretreatment did not influence the decrease of platelets and their accumulation in the lung after tumour cell injection. In contrast, heparin completely prevented the thrombocytopenia and the platelet trapping in the lung. From the present experiments it is concluded that embolic tumour cells lead to early endothelial damage, resulting in local thrombin formation with subsequent irreversible platelet aggregation.

Topics: Animals; Blood Cell Count; Blood Platelets; Carcinoma 256, Walker; Chromium; Chromium Isotopes; Dipyridamole; Embolism; Endothelium; Fibrin; Fibrinogen; Heparin; Injections, Intra-Arterial; Injections, Intravenous; Kidney; Liver; Lung; Neoplasm Metastasis; Platelet Adhesiveness; Rats; Spleen; Thrombin; Thrombocytopenia; Time Factors

Topics: Aged; Angiography; Antigens; Female; Femoral Neck Fractures; Fibrin; Fibrinogen; Fibrinolysis; Heart Failure; Humans; Iodine Radioisotopes; Male; Neoplasm Metastasis; Postoperative Complications; Pulmonary Embolism; Radionuclide Imaging; Sepsis; Thrombophlebitis

Topics: Anticoagulants; Breast Neoplasms; Female; Fibrin; Humans; Neoplasm Metastasis; Venoms

Topics: Adhesiveness; Animals; Blood Platelets; Blood Vessels; Carcinoma 256, Walker; Embolism; Epithelium; Fibrin; Lymphoma; Microscopy, Electron; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neoplastic Cells, Circulating; Rats; Surface Properties

Topics: Animals; Blood Platelets; Capillaries; Carcinoma 256, Walker; Cell Aggregation; Cell Count; Fibrin; Fluorescent Antibody Technique; Goats; Histocytochemistry; Immune Sera; Immunodiffusion; Lung Neoplasms; Male; Methods; Microscopy, Electron; Neoplasm Metastasis; Neoplasms, Experimental; Pulmonary Artery; Rabbits; Rats; Staining and Labeling; Time Factors

Topics: Animals; Anticoagulants; Fibrin; Fibrinolytic Agents; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Warfarin

Topics: Acute Disease; Acute Kidney Injury; Adult; Aged; Agglutination Tests; Arteries; Arteriosclerosis Obliterans; Blood Coagulation Tests; Contraceptives, Oral; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinolysis; Humans; Liver Cirrhosis; Male; Methods; Middle Aged; Neoplasm Metastasis; Protamines; Pulmonary Embolism; Staphylococcus; Sulfates; Thrombosis; Veins

Topics: Adult; Aged; Biguanides; Clofibrate; Coronary Disease; Ethylestrenol; Female; Fibrin; Fibrinogen; Fibrinolysis; Hemagglutination Inhibition Tests; Hemostasis; Humans; Immunoassay; Immunodiffusion; Immunoelectrophoresis; Liver Cirrhosis; Male; Metformin; Middle Aged; Neoplasm Metastasis; Nicotinic Acids; Physical Exertion; Plasminogen; Prostatic Neoplasms; Stimulation, Chemical; Time Factors; Tolazamide

Topics: Aminocaproates; Animals; Coumarins; Fibrin; Heparin; Melanoma; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neoplasms, Vascular Tissue; Tail

Topics: Adenocarcinoma; Aged; Brain Neoplasms; Cell Transformation, Neoplastic; Diagnosis, Differential; Fibrin; Hemangiopericytoma; Hemangiosarcoma; Hemosiderin; Humans; Male; Meningioma; Neoplasm Metastasis; Neoplasm Regression, Spontaneous

Topics: Aminocaproates; Aminocaproic Acid; Animals; Aprotinin; Blood Coagulation; Carcinoma 256, Walker; Carcinoma, Brown-Pearce; Fibrin; Fibrinolysin; Heparin; Hyperlipidemias; Lung Neoplasms; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Rabbits; Radiation Effects; Rats; Research

Topics: Animals; Blood Coagulation; Brain Neoplasms; Carbon Tetrachloride Poisoning; Carcinoma 256, Walker; Female; Fibrin; Heart Neoplasms; In Vitro Techniques; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Mesentery; Neoplasm Metastasis; Neoplastic Cells, Circulating; Rats; Testicular Neoplasms; Wounds and Injuries

Topics: Fibrin; Fibrinolysin; Geriatrics; Humans; Neoplasm Metastasis; Neoplasms; Skin Neoplasms; Stomach Neoplasms; Tongue Neoplasms; Toxicology