fibrin and Neoplasms

The human contact system consists of plasma proteins, which - after contact to foreign surfaces - are bound to them, thereby activating the zymogens of the system into enzymes. This activation mechanism gave the system its name - contact system. It is considered as a procoagulant and proinflammatory response mechanism, as activation finally leads to the generation of fibrin and bradykinin. To date, no physiological processes have been described that are mediated by contact activation. However, contact system factors play a pathophysiological role in numerous diseases, such as cardiovascular diseases, arthritis, colitis, sepsis, and cancer. Contact system factors are therefore an interesting target for new therapeutic options in different clinical conditions.

Topics: Animals; Blood Proteins; Bradykinin; Cardiovascular Diseases; Fibrin; Humans; Inflammation; Neoplasms; Sepsis

Surgical resection continues to be the mainstay treatment for solid cancers even though chemotherapy and immunotherapy have significantly improved patient overall survival and progression-free survival. Numerous studies have shown that surgery induces the dissemination of circulating tumor cells (CTCs) and that the resultant inflammatory response promotes occult tumor growth and the metastatic process by forming a supportive tumor microenvironment (TME). Surgery-induced platelet activation is one of the initial responses to a wound and the formation of fibrin clots can provide the scaffold for recruited inflammatory cells. Activated platelets can also shield CTCs to protect them from blood shear forces and promote CTCs evasion of immune destruction. Similarly, neutrophils are recruited to the fibrin clot and enhance cancer metastatic dissemination and progression by forming neutrophil extracellular traps (NETs). Activated macrophages are also recruited to surgical sites to facilitate the metastatic spread. More importantly, the body's response to surgical insult results in the recruitment and expansion of immunosuppressive cell populations (i.e. myeloid-derived suppressor cells and regulatory T cells) and in the suppression of natural killer (NK) cells that contribute to postoperative cancer recurrence and metastasis. In this review, we seek to provide an overview of the pro-tumorigenic mechanisms resulting from surgery's impact on these cells in the TME. Further understanding of these events will allow for the development of perioperative therapeutic strategies to prevent surgery-associated metastasis.

Topics: Fibrin; Humans; Immunotherapy; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Cells, Circulating; Tumor Microenvironment

The function of the fibrinolytic system was first identified to dissolve fibrin to maintain vascular patency. Connections between the fibrinolytic system and many other physiological and pathological processes have been well established. Dysregulation of the fibrinolytic system is closely associated with multiple pathological conditions, including thrombosis, inflammation, cancer progression, and neuropathies. Thus, molecules in the fibrinolytic system are potent therapeutic and diagnostic targets. This review summarizes the currently used agents targeting this system and the development of novel therapeutic strategies in experimental studies. Future directions for the development of modulators of the fibrinolytic system are also discussed.

Topics: Animals; Antifibrinolytic Agents; Fibrin; Fibrinolysis; Humans; Inflammation; Neoplasms; Thrombosis

Many animal experiments performed worldwide have proven EPR effects However, it is hard to say that the EPR effect works in clinical practice. In the case of hematological malignancies, the administered anticancer agents (ACA) can physically interact with the malignant cells, making it easier to reflect in vitro data. In solid tumors, however, the extravasated ACAs must diffuse evenly within the whole tumor mass. Therefore, the cancer stroma and the tumor mass itself can be obstacles to drug delivery systems (DDS) including antibody therapeutics. We have demonstrated that hypercoagulability caused by cancer forms cancer stroma. We further showed that the more aggressive the cancer, the greater the deposition of insoluble fibrin (IF) in cancer tissue. In this background, we decided to create monoclonal antibody (mAb) that specifically binds to IF. After a long effort, a new and unique IF-specific mAb was developed. Subsequently, anti-IF mAb conjugated with an ACA using a V-L-K linker which can be cut by plasmin. Because plasmin is activated only during IF formation, the ACA is released from the ADC only when the conjugate is bound to the IF. The released ACA may readily get to cancer cells through the stromal obstacle because of its small size. The ACA also damages the capillary that nourish cancer cells. We have named this strategy cancer (CA) stroma (S) targeting (T) therapy, or CAST therapy.

Topics: Animals; Antibodies, Monoclonal; Blood Coagulation; Drug Delivery Systems; Fibrin; Humans; Neoplasms

Although platelets are best known for their role in hemostasis, they are also crucial in development, host defense, inflammation, and tissue repair. Many of these roles are regulated by the immune-like receptors glycoprotein VI (GPVI) and C-type lectin receptor 2 (CLEC-2), which signal through an immunoreceptor tyrosine-based activation motif (ITAM). GPVI is activated by collagen in the subendothelial matrix, by fibrin and fibrinogen in the thrombus, and by a remarkable number of other ligands. CLEC-2 is activated by the transmembrane protein podoplanin, which is found outside of the vasculature and is upregulated in development, inflammation, and cancer, but there is also evidence for additional ligands. In this Review, we discuss the physiological and pathological roles of CLEC-2 and GPVI and their potential as targets in thrombosis and thrombo-inflammatory disorders (i.e., disorders in which inflammation plays a critical role in the ensuing thrombosis) relative to current antiplatelet drugs.

Topics: Amino Acid Motifs; Animals; Collagen; Extracellular Matrix; Fibrin; Fibrinogen; Humans; Inflammation; Lectins, C-Type; Membrane Glycoproteins; Neoplasm Proteins; Neoplasms; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Thrombosis

In 1878, Billroth discovered that tumor cells invest themselves in a fibrin thrombus, and he hypothesized that fibrin promotes tumor growth and invasion. Since then, many observations have supported this concept, showing that many hemostatic factors including fibrinogen, fibrin, and components of the fibrinolytic system have indeed a complex interaction with cancer growth and metastasis. Fibrin promotes cell migration by providing a matrix for tumor cell migration and by interactions with adhesive molecules and integrins. Fibrin-containing vascular endothelial growth factor promotes angiogenesis. Fibrin interacts with platelets and leukocytes, and promotes their respective carcinogenic properties. Fibrinolytic components exert different effects on tumors. Plasmin activates latent growth factors, and breaks down extracellular matrix (ECM), while urokinase plasminogen activator (uPA) and the uPA receptor (uPAR) form complexes with vitronectin and integrins to promote tumor cells to adhere to the ECM. This complex also binds the epidermal growth factor receptor on the tumor cell membrane, and signals the RAF-MEK-ERK pathway. The complex also binds to the G protein-coupled receptors leading to cell proliferation. Plasminogen activator inhibitor 1 (PAI-1) inhibits apoptosis, and increases tumor cell survival. PAI-1 also enhances cell senescence, leading to production of tumorigenic cytokines by the senescence secretome. The presence of uPA/uPAR and PAI-1 represents a strong biomarker for tumor aggressiveness and poor prognosis. Multiple attempts by blocking various carcinogenic steps have shown tumor-suppressing effects in experimental animals, but human responses are uncertain without clinical trials.

Topics: Animals; Blood Platelets; Cell Movement; Fibrin; Fibrinogen; Fibrinolysis; Humans; Integrins; Neoplasms; Protein Binding

Similarities between solid tumor stroma generation, wound healing, chronic inflammation, and associated inflammatory diseases have prompted interest from the time of Virchow. However, it was not until the 1970s that these entities were shown to share important molecular mechanisms. Foundational to all of them is the initiating role of vascular endothelial growth factor (VEGF-A) in increasing vascular permeability to plasma and plasma proteins. Extravasated plasma activates the tissue factor clotting pathway, leading to extravascular deposition of a fibrin gel. Fibrin serves initially as a provisional stroma that provides a favorable substrate for the attachment and migration of tumor cells, as well as host fibroblasts, endothelial, and inflammatory cells. Fibrin and its degradation products have proangiogenic activity with important roles in the generation of new blood vessels and connective tissue stroma. Over time, fibrin is degraded and replaced by vascular and subsequently by dense, relatively avascular collagenous connective tissue, the end-product referred to as desmoplasia in tumors and scar in healed wounds. Fibrin and the mature stroma that replaces it provide a diffusion barrier to chemotherapy and a structural barrier that inflammatory cells must cross to reach tumor cells. Plasma solutes of varying size cross the endothelial cells lining capillaries and venules of normal tissues and "mother" vessels of tumors and wounds by different anatomical pathways. VEGF-A levels fall back to normal as wounds heal but remain perpetually elevated in solid tumors. Thus, tumors may heal centrally but continually initiate new healing activity as they grow and invade surrounding normal tissues.

Topics: Capillary Permeability; Fibrin; Humans; Inflammation; Neoplasms; Thrombosis; Wound Healing

Fibrinogen is a unique protein that is converted into an insoluble fibrin in a single enzymatic event, which is a characteristic feature of fibrinogen due to its susceptibility to fibrinolytic degradation and dissolution. Although thrombosis is a result of activated blood coagulation, no explanation is being offered for the persistent presence of fibrin deposits in the affected organs. A classic example is stroke, in which the thrombolytic therapy is effective only during the first 3-4 h after the onset of thrombosis. This phenomenon can now be explained in terms of the modification of fibrinogen structure induced by hydroxyl radicals generated during the period of ischemia caused, in turn, by the blocking of the blood flow within the obstructed vessels. Fibrinogen modification involves intra-to intermolecular disulfide rearrangement induced by the reductive power of hydroxyl radicals that result in the exposition of buried hydrophobic epitopes. Such epitopes react readily with each other forming linkages stronger than the peptide covalent bonds, thus rendering them resistant to the proteolytic degradation. Also, limited reduction of human serum albumin (HSA) generates hydrophobic polymers that form huge insoluble complexes with fibrinogen. Consequently, such insoluble copolymers can be deposited within the circulation of various organs leading to their dysfunction. In conclusion, the study of protein hydrophobic interactions induced by a variety of nutritional and/or environmental factors can provide a rational explanation for a number of pathologic conditions including cardiovascular, neurologic, and other degenerative diseases including cancer.

Topics: Animals; Arthritis; Cardiovascular Diseases; Diabetes Mellitus; Fibrin; Fibrinogen; Fibrinolysis; Humans; Hydrophobic and Hydrophilic Interactions; Kidney Diseases; Lung Diseases; Models, Biological; Neoplasms; Nervous System Diseases; Polymerization; Protein Interaction Domains and Motifs; Serum Albumin, Human; Solubility; Thrombosis

Cancer induces a systemic hypercoagulable state that elevates the baseline thrombotic risk of affected patients. This hypercoagulable state reflects a complex interplay between cancer cells and host cells and the coagulation system as part of the host response to cancer. Although the tissue factor (TF)/factor VIIa pathway is proposed to be the principal initiator of fibrin formation in cancer patients, clinical studies have not shown a consistent relationship between circulating TF levels (often measured as plasma microvesicle-associated TF) and the risk of thrombosis. A renewed interest in the role of the contact pathway in thrombosis has evolved over the past decade, raising the question of its role in the pathogenesis of thrombotic complications in cancer. Recent observations have documented the presence of activation of the contact system in gastrointestinal, lung, breast and prostate cancers. Although the assays used to measure contact activation differ, and despite the absence of standardization of methodologies, it is clear that both the intrinsic and extrinsic pathways may be activated in cancer. This review will focus on recent findings concerning the role of activation of the contact system in cancer-associated hypercoagulability and thrombosis. An improved understanding of the pathophysiology of these mechanisms may lead to personalized antithrombotic protocols with improved efficacy and safety compared with currently available therapies.

Topics: Animals; Blood Coagulation; Cell-Derived Microparticles; DNA; Factor XII; Fibrin; Glycosaminoglycans; Humans; Neoplasms; Neutrophils; Partial Thromboplastin Time; Platelet Activation; Thromboplastin; Thrombosis

Recent advances in antibody-drug conjugate (ADC) technology have shown considerable promise in targeted cancer therapy. The ADC strategy should be confined to highly toxic anticancer agents and not to ordinary anti-cancer agents (ACAs) because the affinity of monoclonal antibodies (mAbs) diminishes if more than three ACA molecules are conjugated. According to this principle, higher amounts of ADC should be administered so that each of the ACAs is conjugated to the mAbs. Therefore for an ordinary ACA, nanoparticles should be the preferred drug delivery system (DDS). A large body of clinical evidence indicates that abnormal coagulation occurs in a variety of cancer patients, especially in invasive cancers. Tissue factor (TF), expressed on the surface of various cancer cells and tumor vascular endothelial cells, is the trigger protein of extrinsic coagulation resulting in insoluble fibrin formation. We have developed mAbs against TF and human fibrin that reacted only with human fibrin and not with human fibrinogen. We now propose cancer stromal targeting (CAST) therapy and diagnosis, using a cytotoxic agent or radioisotope conjugated to a monoclonal Ab directed at a specific inert constituent of the tumor stroma, as a new modality especially for invasive cancer.

Topics: Antibodies, Monoclonal; Drug Delivery Systems; Fibrin; Humans; Immunoconjugates; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Thromboplastin

The hemostatic system is often subverted in patients with cancer, resulting in life-threatening venous thrombotic events. Despite the multifactorial and complex etiology of cancer-associated thrombosis, changes in the expression and activity of cancer-derived tissue factor (TF) - the principle initiator of the coagulation cascade - are considered key to malignant hypercoagulopathy and to the pathophysiology of thrombosis. However, many of the molecular and cellular mechanisms coupling the hemostatic degeneration to malignancy remain largely uncharacterized. In this review we discuss some of the tumor-intrinsic and tumor-extrinsic mechanisms that may contribute to the prothrombotic state of cancer, and we bring into focus the potential for circulating tumor cells (CTCs) in advancing our understanding of the field. We also summarize the current status of anti-coagulant therapy for the treatment of thrombosis in patients with cancer.

Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation; Blood Platelets; Factor VIIa; Fibrin; Fibrinogen; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplastic Cells, Circulating; Platelet Activation; Prothrombin; Thromboplastin; Thrombosis

Similarities between tumors and the inflammatory response associated with wound healing have been recognized for more than 150 years and continue to intrigue. Some years ago, based on our then recent discovery of vascular permeability factor (VPF)/VEGF, I suggested that tumors behaved as wounds that do not heal. More particularly, I proposed that tumors co-opted the wound-healing response to induce the stroma they required for maintenance and growth. Work over the past few decades has supported this hypothesis and has put it on a firmer molecular basis. In outline, VPF/VEGF initiates a sequence of events in both tumors and wounds that includes the following: increased vascular permeability; extravasation of plasma, fibrinogen and other plasma proteins; activation of the clotting system outside the vascular system; deposition of an extravascular fibrin gel that serves as a provisional stroma and a favorable matrix for cell migration; induction of angiogenesis and arterio-venogenesis; subsequent degradation of fibrin and its replacement by "granulation tissue" (highly vascular connective tissue); and, finally, vascular resorption and collagen synthesis, resulting in the formation of dense fibrous connective tissue (called "scar tissue" in wounds and "desmoplasia" in cancer). A similar sequence of events also takes place in a variety of important inflammatory diseases that involve cellular immunity.

Topics: Blood Coagulation; Cell Movement; Fibrin; Hemostasis; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Stromal Cells; Vascular Endothelial Growth Factor A; Wound Healing

What is the relationship between the wound-healing process and the development of cancer? Malignant tumours often develop at sites of chronic injury, and tissue injury has an important role in the pathogenesis of malignant disease, with chronic inflammation being the most important risk factor. The development and functional characterization of genetically modified mice that lack or overexpress genes that are involved in repair, combined with gene-expression analysis in wounds and tumours, have highlighted remarkable similarities between wound repair and cancer. However, a few crucial differences were also observed, which could account for the altered metabolism, impaired differentiation capacity and invasive growth of malignant tumours.

Topics: Animals; Cicatrix; Epithelium; Extracellular Matrix; Fibrin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Models, Biological; Neoplasms; Neovascularization, Physiologic; Wound Healing

The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is responsible for the degradation of fibrin into soluble degradation products. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). There are 3 types of PAIs described so far but the most important fibrinolytic inhibitor in vivo is PAI type 1 (PAI-1). Among others, the presence of metabolic syndrome and the -675 4G/5G promoter polymorphism are known to be modulators of PAI-1 levels. Besides their fibrinolytic profile, plasmin and plasminogen activators are implicated in tissue proliferation and cellular adhesion, as they can proteolytically degrade the extracellular matrix and regulate the activation of both growth factors and matrix metalloproteinases. By all these means, the fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis and cancer. PAI 1 has been studied in different settings with thrombotic pathophysiology, such as coronary artery disease and ischaemic stroke. Controversial results have been published and concerns about study designs or presence of confounders have been claimed to be responsible of them. Recently, its involvement in adverse thrombotic events related to the modern drug-eluting coronary stents has renewed the interest of its study. PAI-1 also plays an important role in signal transduction, cell adherence, and migration. Indeed, studies of several types of cancers, including breast cancer, have shown that increased uPA and PAI-1 levels are associated with aggressive tumor behavior and poor prognosis. Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus with marked ability to attach and invade the peritoneum. It is one of the most frequent benign gynecological diseases that affect women with pelvic pain or infertility during their reproductive age. Immune system disorders, genetic predisposition, altered peritoneal environment and endometrial alterations are believed to increase the susceptib

Topics: Coronary Artery Disease; Endometriosis; Female; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Matrix Metalloproteinases; Neoplasms; Plasminogen; Plasminogen Activators; Plasminogen Inactivators; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition, is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted therapeutic approach to cancer.

Topics: Animals; Blood Coagulation; Cyclooxygenase 2; Fibrin; Gene Expression Regulation, Neoplastic; Hemostasis; Humans; Membrane Proteins; Models, Genetic; Neoplasms; Plasminogen Activator Inhibitor 1

The hypercoagulability exhibited by most cancer patients leads to serious complications such as venous thromboembolism and contributes to the pathogenesis of tumor growth and metastasis by promoting angiogenesis. The key player in this vicious cycle is tissue factor (TF), the initiator of blood coagulation. Although TF normally safeguards vascular integrity by inducing hemostasis upon injury, abnormal expression of TF in different tumors and related vascular endothelial cells contributes to unnecessary clot formation in cancer patients. Clotting-dependent induction of tumor angiogenesis is primarily mediated by TF-induced generation of thrombin and subsequent deposition of cross-linked fibrin. A cross-linked fibrin network provides a provisional proangiogenic matrix that facilitates blood vessel infiltration. Clotting-independent mechanisms of TF-induced tumor angiogenesis have also been described, mediated primarily by the cytoplasmic tail of the TF receptor. TF activation could contribute to the venous thromboembolism that has been reported as a complication of the use of novel antiangiogenic agents in combination with chemotherapy. Anticoagulants, such as low-molecular-weight heparin, may act to prevent these complications both by interfering with TF-mediated activation of clotting and by directly down-regulating angiogenesis. Thus, TF may prove to be a novel target for cancer therapy.

Topics: Animals; Fibrin; Humans; Neoplasms; Neovascularization, Pathologic; Thrombophilia; Thromboplastin

The transmembrane glycoprotein tissue factor (TF) is the initiator of the coagulation cascade in vivo. When TF is exposed to blood, it forms a high-affinity complex with the coagulation factors factor VII/activated factor VIIa (FVII/VIIa), activating factor IX and factor X, and ultimately leading to the formation of an insoluble fibrin clot. TF plays an essential role in hemostasis by restraining hemorrhage after vessel wall injury. An overview of biological and physiological aspects of TF, covering aspects consequential for thrombosis and hemostasis such as TF cell biology and biochemistry, blood-borne (circulating) TF, TF associated with microparticles, TF encryption-decryption, and regulation of TF activity and expression is presented. However, the emerging role of TF in the pathogenesis of diseases such as sepsis, atherosclerosis, certain cancers and diseases characterized by pathological fibrin deposition such as disseminated intravascular coagulation and thrombosis, has directed attention to the development of novel inhibitors of tissue factor for use as antithrombotic drugs. The main advantage of inhibitors of the TF*FVIIa pathway is that such inhibitors have the potential of inhibiting the coagulation cascade at its earliest stage. Thus, such therapeutics exert minimal disturbance of systemic hemostasis since they act locally at the site of vascular injury.

Topics: Animals; Arteriosclerosis; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Vessels; Disseminated Intravascular Coagulation; Fibrin; Gene Expression Regulation; Humans; Neoplasms; Sepsis; Thromboplastin; Thrombosis

In addition to its primary role in hemostasis and blood coagulation, thrombin is a potent mitogen capable of inducing cellular functions. Therefore, it should come as no surprise that thrombin has proved to be of importance in the behavior of cancer. In this review, we focus on the ability of tissue factor (TF) and thrombin to influence tumor angiogenesis. Both exert their influence on angiogenesis through clotting-dependent and clotting-independent mechanisms: (1). directly affecting signaling pathways that mediate cell functions, and (2). mediating clot formation, thereby providing a growth media for tumor cells. Therefore, anticoagulant drugs may prove efficacious in cancer treatment due to their ability to reduce the characteristic hypercoagulability of cancer and alter the fundamental biology of cancer.

Topics: Fibrin; Humans; Neoplasms; Neovascularization, Pathologic; Thrombin; Thromboplastin; Thrombosis

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

Fibronectin is an extracellular matrix component which appears in different isoforms, due to alternative mRNA splicing of the ED-A, ED-B and III-CS regions and subsequent post-translational modification. It is composed of multiple homologous repeats and contains many functional domains. Because of its ability to interact with many ligands including cells, heparin, fibrin, collagen, DNA, immunoglobulin, fibronectin can play the role in variety of biological processes.

Topics: Collagen; DNA; Fibrin; Fibronectins; Heparin; Humans; Immunoglobulins; Neoplasms; Structure-Activity Relationship

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

Endothelial cells (EC) interact with fibrin at sites of vascular injury, thrombosis, inflammation and tumor growth, whereas they are quiescent when exposed to circulating fibrinogen. To determine the structural basis for specific interaction with fibrin we have characterized the response of EC to fibrin of varying structure. Fibrin was prepared with thrombin, which cleaves both fibrinopeptide A (FPA) and fibrinopeptide B (FPB), with Reptilase, which cleaves only FPA, and with contortrix procoagulant to cleave only FPB. Fibrin with FPB cleavage stimulated release of von Willebrand factor from EC Weibel-Palade bodies and also supported cell spreading. Involvement of the amino terminus of the fibrin beta chain in the response was shown by stimulation of von Willebrand factor release by the peptide beta 15-42. Also, fibrin prepared from a fibrinogen derivative lacking residues 15-42 of the beta chain failed to support EC spreading. EC adhesion was unaffected by the pattern of fibrinopeptide cleavage or by the removal of peptide beta 15-42 from fibrin. The results indicate that separate sites on the fibrin molecule mediate adhesion and spreading, and that the latter requires cleavage of FPB and the new amino terminus of the beta chain. They further suggest that cellular responses to fibrin are regulated by the proteolytic cleavages and conformational changes that convert fibrinogen to fibrin and may also be modulated by plasmic or elastase degradation.

Topics: Amino Acid Sequence; Animals; Cell Adhesion; Endothelium, Vascular; Fibrin; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Humans; Inflammation; Macromolecular Substances; Molecular Sequence Data; Neoplasms; Platelet Adhesiveness; Thrombosis; von Willebrand Factor

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

Topics: Blood Coagulation; Capillary Permeability; Endothelial Growth Factors; Fibrin; Fibrinogen; Humans; Kinetics; Lymphokines; Microcirculation; Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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

Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Arteriosclerosis; Dogs; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Fibrinopeptide A; Humans; Kidney Diseases; Neoplasms; Pregnancy; Pregnancy Complications; Radioimmunodetection; Thrombosis

Proteolytic enzymes have been used to separate and analyze the fibronectin sequences responsible for the multiple interactions between fibronectin and collagens, proteoglycans, cell surfaces, etc. The location of these sequences on the molecule subunits has also been determined. This short article summarizes these results as well as future prospects.

Topics: Cell Membrane; Collagen; Drug Interactions; Fibrin; Fibronectins; Heparin; Neoplasms; Peptide Fragments; Peptide Hydrolases

Tumor stroma formation results from the interaction of tumor cells and their products with the host and certain of its normal defense mechanisms, particularly the clotting and fibrinolytic systems. It is a process in which tumor cells render local venules and veins hyperpermeable with the result that fibrinogen and other proteins extravasate and clot, forming an extravascular crosslinked fibrin gel. Coagulation is mediated by an interaction between extravasated plasma clotting factors and tumor-associated and perhaps other tissue procoagulants. Parallel activation of the fibrinolytic system leads to substantial fibrin turnover, but fibrin nonetheless accumulates in amounts, variable from tumor to tumor, that are sufficient to provide a provisional stroma. This provisional stroma imposes on tumor cells a structure that persists even as tumor cells multiply and as the fibrin provisional stroma is replaced by mature connective tissue. The provisional fibrin stroma also serves to regulate the influx of macrophages, and perhaps other inflammatory cells, but at the same time, and in ways that are not fully understood, facilitates the inward migration of new blood vessels and fibroblasts, integral components of mature tumor stroma. Ascites tumors differ from solid tumors in that fibrin gel is not ordinarily deposited in body cavities and, as a result, there is no provisional stroma to impose an initial structure. Tumor stroma generation resembles the process of wound healing in many respects. However, it differs in the mechanism of its initiation, and in the apparent lack of a role for platelets. It also differs fundamentally in that invading tumor cells continually render new vessels hyperpermeable to plasma, thus perpetuating the cycle of extravascular fibrin deposition. In this sense, tumors behave as wounds that do not heal. Largely neglected in this review has been discussion of the numerous cytokines, mitogens, and growth factors that are widely believed to play important roles in tumor angiogenesis and wound healing; i.e., PDGF, FGF, EGF, TGF alpha, TGF beta, TNF, interferons, etc. This omission has been intentional, and for two reasons. First, these cytokines have already received considerable attention [100,123-128]. Second, it is not yet clear how closely the actions of these molecules, as described in vitro, relate to their functions in vivo. At present we are deluged with a surfeit of factors that have the capacity to induce new blood vessel formatio

Topics: Blood Coagulation; Blood Proteins; Capillary Permeability; Fibrin; Humans; Macrophages; Neoplasms; Neovascularization, Pathologic

Solid tumors must induce new blood vessels if they are to grow beyond minimal size. As an initial step in this process, tumors secrete a vascular permeability factor that renders the local microvasculature hyperpermeable to fibrinogen and to other plasma proteins. Extravasated fibrinogen is rapidly clotted to crosslinked fibrin gel. Over time, this gel is invaded by macrophages, fibroblasts, and endothelial cells and undergoes "organization," such that it is replaced by vascularized granulation tissue and finally by mature connective tissue. This sequence of events is not unique to tumors but occurs in wound-healing and in a wide variety of other disease processes, including some that prominently affect the lung.

Topics: Animals; Blood Vessels; Capillary Permeability; Fibrin; Fibrosis; Humans; Neoplasms; Neovascularization, Pathologic; Wound Healing

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; Collagen; Fibrin; Fibrinolysis; Granulation Tissue; Humans; Neoplasms; Wound Healing

Topics: alpha-Macroglobulins; Animals; Cell Differentiation; Cells, Cultured; Dexamethasone; Enzyme Activation; Female; Fibrin; Fibrinolysis; Hormones; Humans; Interferons; Macrophages; Male; Monocytes; Neoplasms; Ovulation; Plasminogen; Plasminogen Activators; Plasminogen Inactivators; Protease Inhibitors; Proteins; Spermatogenesis; Urokinase-Type Plasminogen Activator

Considerable interest in plasminogen activators as human thrombolytic drugs has stimulated rapid biotechnologic progresses. These enzymes have been classified in two immunochemically distinct groups: "urokinase-like" activators or u-PA which do not interact with fibrin and "tissue activator-like" activators or t-PA which interact with fibrin. Plasminogen activators are widely distributed in normal and malignant tissues and they are implicated in various physiological and pathological processes. They maintain the functional integrity of the vascular system and their presence may be of importance in tissue remodeling and cell migration. Urokinase and streptokinase are used in human thrombolytic therapy. However, the properties displayed by t-PA suggest that this enzyme may be a superior fibrinolytic agent. The primary structures of urokinase and t-PA are known; both enzymes have been synthesized by DNA technology. In order to produce t-PA in large quantities by gene cloning, intensive studies are conducted by pharmaceutical industries. Clinical trials using t-PA for dissolving thrombi in coronary heart disease, strokes and pulmonary embolism are in progress. This review presents the molecular and structural properties of plasminogen activators, as well as related physiological, pathological and therapeutic aspects.

Topics: Animals; Fibrin; Fibrinolysis; Humans; Models, Molecular; Molecular Weight; Neoplasms; Plasminogen Activators; Protein Conformation; Substrate Specificity; Tissue Distribution; Urokinase-Type Plasminogen Activator

The existence of a system in the human body capable of inducing the dissolution of endogenous pathologically formed thrombi was appreciated in ancient times. Considered in detail in this article are the data that have elucidated the physiologic regulation of which plasmin formation is dependent on, the plasma concentration of plasminogen, availability of activators of plasminogen in the plasma and surrounding tissue environment, the concentration of naturally present inhibitors, and the existence of fibrin in the circulation. Important in this rapidly progressive scientific discipline is consideration of the factors which control the synthesis of the components of this proteolytic enzyme system. Recently abundant information has indicated that this plasminogen-plasmin proteolytic enzyme system can be utilized therapeutically. Knowledge of the mechanisms of this system has permitted identification of agents that can be exogenously administered to releave thrombotic obstruction to blood flow in the venous (pulmonary emboli, deep vein thrombosis) and arterial (peripheral and central vessels) circulatory systems. Particularly important is the demonstration that thrombolytic agents can directly attack and alleviate the immediate cause of acute myocardial infarction. As a result of the innovations in the present decade, it is evident that the plasminogen system can be advantageously employed to reverse the pathologic effects of all thrombotic diseases.

Topics: alpha 1-Antitrypsin; alpha-2-Antiplasmin; alpha-Macroglobulins; Antifibrinolytic Agents; Antithrombin III; Arterial Occlusive Diseases; Arteriosclerosis; Complement C1 Inactivator Proteins; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Kidney Diseases; Liver Diseases; Myocardial Infarction; Neoplasms; Plasminogen; Pulmonary Embolism; Thrombophlebitis

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

From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders.

Topics: Animals; Anti-Inflammatory Agents; Antigens; Blood Coagulation; Blood Coagulation Factors; Cell Line; Factor V; Factor VII; Factor X; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Guinea Pigs; Humans; Hypersensitivity, Delayed; Immunologic Deficiency Syndromes; Infections; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monocytes; Neoplasms; Neutrophils; Rabbits; Rats; T-Lymphocytes; Thromboembolism; Thromboplastin; Warfarin

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Platelets; Disseminated Intravascular Coagulation; Factor X; Fibrin; Fibrinolysis; Humans; Neoplasms; Neovascularization, Pathologic; Thrombophlebitis; Thromboplastin

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

Topics: Adhesiveness; Animals; Arteriosclerosis; Basement Membrane; Blood Coagulation; Blood Vessel Prosthesis; Blood Viscosity; Capillaries; Capillary Permeability; Decompression Sickness; Endothelium; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Gels; Homeostasis; Humans; Hydrogen-Ion Concentration; Neoplasms; Polysaccharides; Protein Conformation; Protein Precursors; Rheology

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: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Blood Vessels; Cardiopulmonary Bypass; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Infant, Newborn; Kidney Diseases; Myocardial Infarction; Neoplasms; Pregnancy; Pulmonary Embolism; Syndrome; Thrombin; Thrombophlebitis; Thrombosis

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

Topics: Amino Acids; Blood Coagulation; Blood Platelets; Carbohydrates; Electrophoresis, Polyacrylamide Gel; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Liver Diseases; Molecular Weight; Neoplasms; Placenta

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

Topics: Animals; Anticoagulants; Blood Coagulation Factors; Fibrin; Hemostatics; Lymphatic Metastasis; Neoplasms; Neoplasms, Experimental; Thromboplastin

Most central venous catheter (CVC)-related deep vein thromboses (DVT) are asymptomatic and their incidence and clinical relevance are still under debate. Data on CVC-related fibrin sheaths are scarce. We investigated the incidence of asymptomatic DVT and fibrin sheaths in cancer patients with long-term CVC implantation who underwent Doppler ultrasound surveillance at 1, 6, and 12 months after implantation. Effects of low-weight molecular heparin (LWMH) therapy on DVT and fibrin sheaths were also analyzed.. This prospective study was performed on a large cohort (n = 400) of patients with cancer aged >18 requiring long-term CVC implantation for chemotherapy infusion. CVC was implanted by a trained qualified staff, according to standardized protocol in a specific surgery. Patients underwent ultrasound examination at 1 and 6 months after CVC implantation to detect 'early' (1 month) and 'late' (6 months) asymptomatic DVT or fibrin sheaths incidence. Sixty-nine patients underwent US examination also 12 months after CVC implantation.. The incidence of CVC-related thrombosis was 0.10 events per 1000 catheter days. Anticoagulation therapy with LWMH resolved 50% of DVT, but no CVC needed removing. Incidence of new onset fibrin sheaths was 0.71 events per 1000 catheter days. Fibrin sheaths resolution occurred independently of LWMH therapy.. The incidence of asymptomatic DVT in our patients with long-term CVC is very low and does not represent per se an indication for removal of functioning CVC in patients with cancer. Fibrin sheaths are frequent (13%) and never associated with CVC dysfunction.. Asymptomatic DVT and fibrin sheaths do not represent per se an indication for removal of functioning CVC in cancer patients who need central vein access.

Topics: Aged; Female; Fibrin; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Neoplasms; Prospective Studies; Ultrasonography, Doppler, Color; Upper Extremity Deep Vein Thrombosis

This study was undertaken to determine the role of low-dose urokinase infusions in treating fibrinous occlusions of venous access devices (VADs) in cancer patients.. Forty-two patients with VAD occlusions refractory to routine urokinase instillations were documented by x-ray (cathetergram) to have fibrin sleeves at the catheter tips. They were randomized to receive infusions of either urokinase (40,000 U/h) or urokinase with heparin (320 U/h) through their catheters. After 1, 3, 6, and 12 hours of treatment, the function of the VADs was reassessed. Whenever the obstruction had been relieved, the infusion was stopped and a repeat cathetergram was performed. The status of the unoccluded catheters was followed to determine the longevity of the restored function.. Twenty-one catheters were treated with urokinase alone and 21 with the combination of urokinase and heparin. In each group, 16 VADs opened within 12 hours of treatment and five did not. By actuarial analysis, the probability was only 0.28 that a reopened catheter would reocclude within 6 months.. Low-dose urokinase infusions can restore function to the majority of catheters occluded by fibrin sleeves. Adding heparin to the urokinase does not enhance the efficacy of the infusions. The restored function often persists until the VADs are removed.

Topics: Adult; Aged; Antineoplastic Agents; Catheters, Indwelling; Double-Blind Method; Female; Fibrin; Fibrinolytic Agents; Heparin; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Prospective Studies; Treatment Outcome; Urokinase-Type Plasminogen Activator

Clinical trials to evaluate the potential of adoptive immunotherapy in cancer patients have been restricted to the use of lymphoid effector cells. Of the other probably even more important host defense system against tumor growth, the mono-nuclear phagocyte system, only monocytes (mo) have been reinfused which, however, represent immature precursor cells and acquire full functional competence only upon further maturation. This is a report on 7 patients who received autologous macrophages (MO) grown in vitro from blood mo and activated by interferon-gamma (IFN gamma). Mononuclear cells were isolated from whole blood by cytapheresis and cultured for 7 days with 2% autologous serum on hydrophobic Teflon foils. Eighteen house before cell harvest, recombinant human IFN gamma was added at 200 IU/ml. Mo-derived MO were purified by counter-current elutriation. Starting with 10(8) MO cells, therapy was escalated up to the maximal number of MO obtainable from one single preparation cycle. Currently, 26 therapies have been performed with the maximal dose being 1.7 x 10(9) MO per infusion. Except for low grade fever (less than 38 degrees C), MO autografts were well tolerated, with no side effects observed. Biological response was followed by analyzing the serum levels of beta 2-microglobulin, neopterin, interleukin-6, tumor necrosis factor, and lysozyme. While in 3 out of 7 patients serum neopterin increased in response to MO therapy, other biological response parameters remained at pretreatment levels. Radiolabeled MO were shown to first accumulate in the lungs, then to pool into liver and spleen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biopterins; Cell Movement; Cells, Cultured; Cytapheresis; Fibrin; Fibrinogen; Humans; Immunotherapy, Adoptive; Interferon-gamma; Macrophage Activation; Macrophages; Monocytes; Neoplasms; Neopterin; Pilot Projects; Recombinant Proteins; Transplantation, Autologous

Thrombi in cerebral large vessel occlusion associated with active cancer are often fibrin and platelet-rich white thrombi. However, evaluating the thrombus composition in a short time before thrombectomy is often ineffective. We sought to determine factors related to white thrombi in acute ischemic stroke due to large vessel occlusion in cancer patients.. Consecutive cancer patients undergoing thrombectomy for acute ischemic stroke due to large vessel occlusion between January 2018 and May 2022 were retrospectively reviewed. The patients were classified into white thrombus and red thrombus groups on the basis of the pathological findings of retrieved thrombi. Patient characteristics and laboratory findings were compared between the two groups.. In acute ischemic stroke in cancer patients, active cancer, no internal carotid artery occlusion, and higher D-dimer levels (≥3.5 μg/mL) may be associated with occlusion with fibrin and platelet-rich white thrombi.

Topics: Arterial Occlusive Diseases; Brain Ischemia; Fibrin; Humans; Ischemic Stroke; Neoplasms; Retrospective Studies; Stroke; Thrombectomy; Thrombosis

A bidirectional association exists between metastatic dissemination and the hypercoagulable state associated with many types of cancer. As such, clinical studies have provided evidence that markers associated with elevated levels of coagulation and fibrinolysis correlate with decreased patient survival. However, elucidating the mechanisms underpinning the effects of different components of the coagulation system on metastasis formation is challenging both in animal models and 2D models lacking the complex cellular interactions necessary to model both thrombosis and metastasis. Here, an in vitro, 3D, microvascular model for observing the formation of fibrin thrombi is described, which is in turn used to study how different aspects of the hypercoagulable state associated with cancer affect the endothelium. Using this platform, cancer cells expressing ICAM-1 are shown to form a fibrinogen-dependent bridge and transmigrate through the endothelium more effectively. Cancer cells are also demonstrated to interact with fibrin thrombi, using them to adhere, spread, and enhance their extravasation efficiency. Finally, thrombin is also shown to enhance cancer cell extravasation. This system presents a physiologically relevant model of fibrin clot formation in the human microvasculature, enabling in-depth investigation of the cellular interactions between cancer cells and the coagulation system affecting cancer cell extravasation.

Topics: Animals; Blood Coagulation; Fibrin; Fibrinogen; Hemostatics; Humans; Neoplasms; Thrombin; Thrombosis

Coagulation proteases and the generation of thrombin are increased in tumors. In addition, chemotherapeutic agents commonly used to treat malignant cancers can exacerbate cancer-associated thromboses. Thrombin can modify tumor cell behavior directly through the activation of protease-activated receptors (PAR) or indirectly by generating fibrin matrices. In addition to its role in generating fibrin to promote hemostasis, thrombin acts directly on multiple effector cells of the immune system impacting both acute and chronic inflammatory processes. Thrombin-mediated release of interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 leads to the accumulation of multiple tumor-infiltrating immunosuppressive cell populations including myeloid derived suppresser cells, M2-like macrophages, and T regulatory cells. Ablation of PAR-1 from the tumor microenvironment, but not the tumor, has been shown to dramatically reduce tumor growth and metastasis in multiple tumor models. Thrombin-activated platelets release immunosuppressive cytokines including transforming growth factor-β that can inhibit natural killer cell activity, helping tumor cells to evade host immunosurveillance. Taken together, there is strong evidence that thrombin influences cancer progression via multiple mechanisms, including the tumor immune response, with thrombin emerging as a target for novel therapeutic strategies for cancer.

Topics: Fibrin; Humans; Immunity; Neoplasms; Receptor, PAR-1; Thrombin; Tumor Microenvironment

Tumours or tumour-like lesions around the aortic valve are relatively rare and are difficult to diagnose. We report an interesting case of calcified thrombi in the Valsalva sinuses and coronary cusps that mimicked an aortic valve tumour. A 68-year-old man presented with a 20-mm calcified mass in the non-coronary and left-coronary cusps extending to their corresponding Valsalva sinuses, which was detected by echocardiography and contrast-enhanced computed tomography. The lesions were resected to establish the diagnosis and prevent systemic embolization. Intraoperative and histopathological examination revealed an atrophied non-coronary leaflet and calcified atherosclerotic lesions of the Valsalva sinuses and contiguous parts of the cusps, with ulceration and fibrin thrombi. The lesions were resected and aortic valve replacement was performed to avoid aortic valve dysfunction. The patient's atrial fibrillation was controlled, and anticoagulants were discontinued 3 months postoperatively. Surgery to establish the diagnosis and to prevent systemic thromboembolism was thought to be reasonable, even in the absence of valvular dysfunction.

Topics: Aged; Anticoagulants; Aortic Valve; Fibrin; Humans; Male; Neoplasms; Sinus of Valsalva; Thrombosis

Magnetic resonance imaging (MRI) is a clinical imaging modality that provides high-resolution images of soft tissues, including cancerous lesions. Stable gadolinium(III) chelates have been used as contrast agents (CA) in MRI to enhance the contrast between the tissues of interest and surrounding tissues for accurate diagnostic imaging. Magnetic resonance molecular imaging (MRMI) of cancer requires targeted CA to specifically elucidate cancer-associated molecular processes and can provide high-resolution delineation and characterization of cancer for precision medicine. The main challenge for MRMI is the lack of sufficient sensitivity to detect the low concentration of the cellular oncogenic markers. In addition, targeted CA must satisfy regulatory safety requirements prior to clinical development. Up to now, there is no FDA-approved targeted CA for MRMI of cancer.In this Account, we discuss the latest developments in the design and development of clinically translatable targeted CA for MRMI of cancer, with an emphasis on our own research. The primary limitation of MRMI can be overcome by designing small molecular targeted CA to target abundant cancer-specific targets found in the tumor microenvironment (TME). For example, aggressive tumors have a unique extracellular matrix (ECM) composed of oncoproteins, which can be used as targetable markers for MRMI. We have designed and prepared small peptide conjugates of clinical contrast agents, including Gd-DTPA and Gd-DOTA, to target fibrin-fibronectin clots in tumors. These small molecular CA have been effective in enhancing MRMI detection of solid tumors and have demonstrated the ability to detect submillimeter cancer micrometastases in mouse tumor models, exceeding the detection limit of current clinical imaging modalities. We have also identified extradomain B fibronectin (EDB-FN), an oncofetal subtype of fibronectin, as a promising TME target to leverage in the design and development of small peptide targeted CA for clinical translation. The expression level of EDB-FN is correlated with invasiveness of cancer cells and poor patient survival of multiple cancer types. ZD2 peptide with a sequence of seven amino acids (TVRTSAD) was identified to specifically bind to the EDB protein fragment. Several ZD2 conjugates of macrocyclic GBCA, including Gd-DOTA and Gd(HP-DO3A), have been synthesized and tested in mouse tumor models. ZD2-N3-Gd(HP-DO3A) (MT218) with a high r

Topics: Amino Acids; Animals; Contrast Media; Fibrin; Fibronectins; Gadolinium; Gadolinium DTPA; Heterocyclic Compounds; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mice; Molecular Imaging; Neoplasms; Oncogene Proteins; Organometallic Compounds; Peptides; Tumor Microenvironment

The in vitro culture of primordial follicles is the only available option for preserving fertility in prepubertal girls with malignant tumors. The cultivation of primordial follicles in scaffolds as artificial ovaries is a promising approach for this.. Dissociated follicles were placed into an artificial ovarian scaffold composed of fibrinogen and thrombin. The follicles were cultured in a dish dedicated to live cell imaging and observed for growth using immunofluorescence and development via optical microscopy. The morphology of the follicles in the scaffold was three-dimensionally reconstructed using the Imaris software. Growth and development were also quantified.. The morphology of artificial ovaries began to degrade over time. Within approximately 7 days, primordial follicles were activated and grew into secondary follicles. A comparison of optical and confocal microscopy results revealed the superior detection of live cells using confocal microscopy. The three-dimensional reconstruction of the confocal microscopy data enabled the automatic enumeration and evaluation of the overall morphology of many follicles.. The novel artificial ovary-enabled primordial follicles to enter the growth cycle after activation and grow into secondary follicles. The use of a fibrin scaffold as a carrier preserves the developmental potential of primordial germ cells and is a potentially effective method for preserving fertility in prepubertal girls.

Topics: Bioengineering; Female; Fertility Preservation; Fibrin; Fibrinogen; Humans; Neoplasms; Ovary; Thrombin

The procoagulant state in cancer increases the thrombotic risk, and underlying cancer could affect treatment strategies and outcomes in patients with ischemic stroke. However, the histopathological characteristics of retrieved thrombi in patients with cancer have not been well studied. This study aimed to assess the histopathological difference between thrombi in patients with and without cancer.. We studied consecutive patients with acute major cerebral artery occlusion who were treated with endovascular therapy between October 2010 and December 2016 in our single-center registry. The retrieved thrombi were histopathologically investigated with hematoxylin and eosin and Masson's trichrome staining. The organization and proportions of erythrocyte and fibrin/platelet components were studied using a lattice composed of 10×10 squares.. Of the 180 patients studied, 17 (8 women, age 76.5±11.5 years) had cancer and 163 (69 women, age 74.1±11.2 years) did not. Those with cancer had a higher proportion of fibrin/platelets (56.6±27.4% vs 40.1±23.9%, p=0.008), a smaller proportion of erythrocytes (42.1±28.3% vs 57.5±25.1%, p=0.019), and higher serum D-dimer levels (5.9±8.2 vs 2.4±4.3 mg/dL, p=0.005) compared with the non-cancer cases. Receiver operating characteristic curve analysis showed the cut-off ratio of fibrin/platelet components related to cancer was 55.7% with a sensitivity of 74.8%, specificity 58.8% and area under the curve (AUC) value of 0.67 (95% CI 0.53 to 0.81), and the cut-off ratio of erythrocyte components was 44.7% with a sensitivity of 71.2%, specificity 58.9% and AUC value of 0.66 (95% CI 0.51 to 0.80).. Thromboemboli of major cerebral arteries in patients with cancer were mainly composed of fibrin/platelet-rich components.

Topics: Aged; Aged, 80 and over; Female; Fibrin; Humans; Ischemic Stroke; Male; Middle Aged; Neoplasms; Thrombectomy

Molecular medical imaging is intended to increase the accuracy of diagnosis, particularly in cardiovascular and cancer-related diseases, where early detection could significantly increase the treatment success rate. In this study, we present mixed micelles formed from four building blocks as a magnetic resonance imaging targeted contrast agent for the detection of atheroma and cancer cells. The building blocks are a gadolinium-loaded DOTA ring responsible for contrast enhancement, a fibrin-specific CREKA pentapeptide responsible for targeting, a fluorescent dye and DSPE-PEG

Topics: Cell Line; Contrast Media; Fibrin; Fluorescent Dyes; Heterocyclic Compounds; Human Umbilical Vein Endothelial Cells; Humans; Intravital Microscopy; Magnetic Resonance Imaging; MCF-7 Cells; Micelles; Molecular Imaging; Neoplasms; Organometallic Compounds; Phosphatidylethanolamines; Plaque, Atherosclerotic; Polyethylene Glycols

The biophysical properties of extracellular matrices (ECM) are known to regulate cell behavior, however decoupling cell behavior changes due to the relative contributions of material microstructure versus biomechanics or nutrient permeability remains challenging, especially within complex, multi-material matrices. We developed four gelatin-fibrin interpenetrating network (IPN) formulations which are identical in composition but possess variable gelatin molecular weight distributions, and display differences in microstructure, biomechanics, and diffusivity. In this work we interrogate the response of multicellular tumor spheroids to these IPN formulations and found that a high stiffness, gelatin-network dominated IPNs impeded remodeling and invasion of multicellular tumor spheroids; whereas relatively lower stiffness, fibrin-network dominated IPNs permitted protease-dependent remodeling and spheroid invasion. Cell proliferation correlated to nutrient diffusivity across tested IPN formulations. These findings demonstrate the complexity of ECM IPNs, relative to single polymer matrices, and highlight that cell response does not derive from a single aspect of the ECM, but rather from the interplay of multiple biomechanical properties. The methodology developed here represents a framework for future studies which aim to characterize cellular phenotypic responses to biophysical cues present within complex, multi-material matrices.

Topics: Fibrin; Gelatin; Humans; Hydrogels; Neoplasms; Polymers

Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H

Topics: Animals; Biocompatible Materials; Calcium Carbonate; Female; Fibrin; Gels; Humans; Immunity; Immunotherapy; Luminescent Measurements; Melanoma, Experimental; Mice, Inbred C57BL; Nanoparticles; Neoplasm Recurrence, Local; Neoplasms; Phagocytosis

A novel near-infrared fluorescent light-up probe with a tumor-homing pentapeptide, CREKA (Cys-Arg-Glu-Lys-Ala), specifically binds to fibrin-fibronectin complexes was rationally designed and developed for biomedical imaging. Its superior practical applications in tumor imaging and drug-induced liver injury detection are well demonstrated for the first time.

Topics: A549 Cells; Aniline Compounds; Animals; Benzopyrans; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Female; Fibrin; Fibronectins; Fluorescent Dyes; Humans; Mice, Inbred BALB C; Microscopy, Fluorescence; Neoplasms; Oligopeptides

Compact fibrin clots relatively resistant to lysis are observed in patients at increased risk of venous thromboembolism (VTE) including malignancy. The citrullinated histone H3 (H3Cit) predicts VTE in cancer patients.. We performed a cohort study to investigate whether abnormal clot properties predict cancer diagnosis following unprovoked VTE.. In 369 consecutive patients aged <70 years without malignancy detected during routine screening, we determined plasma clot permeability (K. During follow-up (median, 37; interquartile range, 33-39 months), malignancy was diagnosed in 22 patients (6%), who were older. This group had denser fibrin networks (-13% K. Prothrombotic clot properties following unprovoked VTE might help identify patients at risk of a diagnosis of cancer within the first 3 years of follow-up.

Topics: Adult; Biomarkers; Citrullination; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Histones; Humans; Male; Middle Aged; Neoplasms; P-Selectin; Permeability; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; Thrombin; Time Factors; Venous Thromboembolism

Accelerated formation of fibrin clots in a tumor microenvironment can be used for targeted delivery of interferon gamma (IFNγ) to tumor cells. Here, we selected cysteine-arginine-glutamic acid-lysine-alanine (CREKA) as the fibrin clot-binding peptide and designed 2 types of fusion proteins for tumor targeting. The CREKA peptide was fused to IFNγ's C-terminus, with or without a matrix metalloproteinase-2 (MMP2)-cleavable linker (IFNγ-mmp-CREKA or IFNγ-CREKA, respectively). The former was designed to release IFNγ from IFNγ-mmp-CREKA bound to fibrin clots, to ensure IFNγ's function in the tumor milieu. IFNγ-activated sequence-dependent reporter gene expression in B16-BL6 cells revealed that the biological activities of IFNγ-CREKA and IFNγ were comparable, whereas that of IFNγ-mmp-CREKA was approximately 60% that of IFNγ. Plasma concentrations of IFNγ-CREKA and IFNγ-mmp-CREKA remained at effective levels for at least 4 weeks after gene transfer into mice. After gene transfer to tumor-bearing mice, intratumoral concentration of IFNγ in pCpG-IFNγ-mmp-CREKA group was tended to be higher than those of the other groups. Inhibition of colon-26 tumor growth was significantly more with gene transfer of IFNγ-mmp-CREKA than with IFNγ or IFNγ-CREKA. These results indicate that targeted delivery of IFNγ to fibrin clots through IFNγ-mmp-CREKA fusion can enhance the therapeutic efficacy of IFNγ in cancer gene therapy.

Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Dose-Response Relationship, Drug; Drug Delivery Systems; Fibrin; Genetic Therapy; Interferon-gamma; Male; Mice; Mice, Inbred BALB C; Neoplasms; Recombinant Fusion Proteins; Xenograft Model Antitumor Assays

Essentials Cancer cachexia and cancer-associated thrombosis have not previously been mechanistically linked. We assessed thrombin generation and coagulation parameters in cachectic C26 tumor-bearing mice. C26 mice are hypercoagulable, partially corrected by blocking tumor derived interleukin-6. Coagulability and anti-inflammatory interventions may be clinically important in cancer cachexia.. Background Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer, which have not previously been mechanistically linked. The colon 26 (C26) carcinoma is a well-established mouse model of complications of advanced cancer cachexia, partially dependent on high levels of interleukin-6 (IL-6) produced by the tumor. Objectives To assess if cancer cachexia altered the coagulation state and if this was attributable to tumor IL-6 production. Methods In male BALB/c*DBA2 (F1 hybrid) mice with a C26 tumor we used modified calibrated automated thrombogram and fibrin generation (based on overall hemostatic potential) assays to assess the functional coagulation state, and also examined fibrinogen, erythrocyte sedimentation rate (ESR), platelet count, tissue factor pathway inhibitor (TFPI) and hepatic expression of coagulation factors by microarray. C26 mice were compared with non-cachectic NC26, pair-fed and sham control mice. IL-6 expression in C26 cells was knocked down by lentiviral shRNA constructs. Results C26 mice with significant weight loss and highly elevated IL-6 had elevated thrombin generation, fibrinogen, ESR, platelets and TFPI compared with all control groups. Fibrin generation was elevated compared with pair-fed and sham controls but not compared with NC26 tumor mice. Hepatic expression of coagulation factors and fibrinolytic inhibitors was increased. Silencing IL-6 in the tumor significantly, but incompletely, attenuated the increased thrombin generation, fibrinogen and TFPI. Conclusions Cachectic C26 tumor-bearing mice are in a hypercoagulable state, which is partly attributable to IL-6 release by the tumor. The findings support the importance of the coagulation state in cancer cachexia and the clinical utility of anti-inflammatory interventions.

Topics: Animals; Blood Coagulation; Cachexia; Cell Line, Tumor; Disease Models, Animal; Fibrin; Fibrinogen; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Interleukin-6; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasm Transplantation; Neoplasms; Thrombin; Tissue Array Analysis

Interactions between malignant and stromal cells and the 3D spatial architecture of the tumor both substantially modify tumor behavior, including the responses to small molecule drugs and biological therapies. Conventional 2D culture systems cannot replicate this complexity. To overcome these limitations and more accurately model solid tumors, we developed a highly versatile 3D PEG-fibrin hydrogel model of human lung adenocarcinoma. Our model relevantly recapitulates the effect of oncolytic adenovirus; tumor responses in this setting nearly reproduce those observed in vivo. We have also validated the use of this model for complex, long-term, 3D cultures of cancer cells and their stroma (fibroblasts and endothelial cells). Both tumor proliferation and invasiveness were enhanced in the presence of stromal components. These results validate our 3D hydrogel model as a relevant platform to study cancer biology and tumor responses to biological treatments.

Topics: Adenoviridae; Animals; Cell Line, Tumor; Cell Proliferation; Female; Fibrin; Human Umbilical Vein Endothelial Cells; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Mice, SCID; Models, Biological; Neoplasm Invasiveness; Neoplasms; Oncolytic Viruses; Organoids; Phenotype; Polyethylene Glycols; Stromal Cells; Tumor Microenvironment

Effective drug delivery to a tumor depends on favorable blood perfusion within the tumor. As an important component of tumor extracellular matrix, fibrin is abundant near tumor vessels. Inspired by the distinct distribution pattern and vessel-dependent production of fibrin, we hypothesized that fibrin depletion in tumors decompresses tumor vessels to improve tumor blood perfusion and accordingly enhance drug delivery to tumors rich in vessels. In the present study, we attempted to employ a clinically used thrombolytic drug, recombinant tissue plasminogen activator (rtPA), to modulate fibrin deposition in tumors. We then combined this drug with a nanoparticle drug delivery system for tumor therapy. RtPA treatment (25 mg/kg/d i. p. administration for two weeks) successfully depleted fibrin deposition and enhanced blood perfusion within A549 tumor xenografts. Furthermore, rtPA treatment also improved the in vivo delivery of 115-nm nanoparticles to tumor tissues. Finally, rtPA combined with therapeutic agent-loaded nanoparticles resulted in the most effective shrinkage of A549 tumor xenografts compared with the control groups. Overall, the present study provides a new strategy to enhance the delivery of nanotherapeutics to tumors rich in vessels.

Topics: A549 Cells; Animals; Drug Delivery Systems; Fibrin; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Paclitaxel; Proteolysis; Recombinant Proteins; Tissue Plasminogen Activator; Tumor Microenvironment

Mammalian cell culture in monolayers is widely used to study various physiological and molecular processes. However, this approach to study growing cells often generates unwanted artifacts. Therefore, cell culture in a three-dimensional (3D) environment, often using extracellular matrix components, emerged as an interesting alternative due to its close similarity to the native in vivo tissue or organ. We developed a 3D cell culture system using two compartments, namely (i) a central compartment containing cancer cells embedded in a collagen gel acting as a pseudo-primary macrospherical tumor and (ii) a peripheral cell-free compartment made of a fibrin gel, i.e. an extracellular matrix component different from that used in the center, in which cancer cells can migrate (invasion front) and/or form microspherical tumors representing secondary or satellite tumors. The formation of satellite tumors in the peripheral compartment is remarkably correlated to the known aggressiveness or metastatic origin of the native tumor cells, which makes this 3D culture system unique. This cell culture approach might be considered to assess cancer cell invasiveness and motility, cell-extracellular matrix interactions and as a method to evaluate anti-cancer drug properties.

Topics: Animals; Cell Culture Techniques; Cell Movement; Collagen; Extracellular Matrix; Fibrin; Humans; Imaging, Three-Dimensional; Neoplasm Invasiveness; Neoplasms

Fibrin deposition plays an important role in the formation of mature tumor stroma and provides a facilitating scaffold for tumor angiogenesis. This study investigates the potential of the (111)In-labeled fibrin-binding peptide EPep for SPECT imaging of intratumoral fibrin deposition. (111)In-EPep and negative control (111)In-NCEPep were synthesized and characterized in vitro. In vivo SPECT images and ex vivo biodistribution profiles and autoradiographs were obtained in a fibrin-rich BT-20 breast cancer mouse model. Furthermore, biodistribution profiles were obtained in the fibrin-poor MDA-MD-231 model. In vitro, (111)In-EPep displayed significantly more binding than (111)In-NCEPep toward human and mouse derived fibrin. SPECT/CT images displayed a marked SPECT signal in the tumor area for BT-20 tumor bearing mice injected with EPep but not for mice injected with NCEPep. Biodistribution profiles of BT-20 tumor bearing mice 3 h post-tracer injection showed significantly higher tumor uptake for EPep with respect to NCEPep (0.39 ± 0.14 and 0.11 ± 0.03% ID g(-1), respectively), whereas uptake in other organs was similar for EPep and NCEPep. Autoradiography of BT-20 tumor sections displayed a high signal for EPep which colocalized with intratumoral fibrin deposits. Histological evaluation of MDA-MB-231 tumor sections displayed no significant tumor stroma and only minute fibrin deposits. Biodistribution profiles in MDA-MB-231 tumor bearing mice 3 h post-injection showed EPep tumor uptake (0.14 ± 0.04% ID g(-1)) which was significantly lower with respect to EPep BT-20 tumor uptake, indicating fibrin-specificity of EPep tumoral uptake. In conclusion, this work demonstrates the potential of EPep SPECT imaging for visualization of tumoral fibrin deposition.

Topics: Animals; Cell Line, Tumor; Female; Fibrin; Humans; Mice; Mice, Inbred BALB C; Neoplasms; Peptides; Radiography; Tomography, Emission-Computed, Single-Photon

Molecular intervention during transient stages of various metastatic pathways may lead to development of promising therapeutic technologies. One of such involves soluble fibrin (sFn) that has been implicated as a cross-linker between circulating blood or tumor cells and endothelial cell receptors, promoting cell arrest on the endothelium during circulation. sFn generation is a result of thrombin-mediated fibrinogen (Fg) cleavage due to either vascular injuries or a tumor microenvironment. For cancer therapy, thrombin-mediated conversions of Fg to sFn thus serve as potential intervention points to decrease circulating tumor cell adhesion to the endothelium and subsequent metastatic events. The purpose of this work was to investigate the function of an anti-thrombin oligonucleotide aptamer in reducing tumor cell arrest. Both molecular and cellular interactions were examined to demonstrate the binding and inhibitory effects of anti-thrombin aptamer. The results show that the aptamer is capable of inhibiting thrombin-mediated Fg conversion, thereby reducing sFn-mediated tumor cell adhesion in a concentration-dependent manner. Notably, the aptamer is able to bind thrombin under dynamic flow conditions and reduce tumor cell adhesive events at various physiological shear rates. This study further indicates that oligonucleotide aptamers hold great promise as therapeutic regulators of tumor cell adhesion, and consequently, metastatic activity.

Topics: Aptamers, Nucleotide; Cell Adhesion; Electrophoresis, Polyacrylamide Gel; Endothelium; Fibrin; Humans; Neoplasms; Surface Plasmon Resonance; Thrombin; Tumor Cells, Cultured

Many patients with malignant diseases are frequently complicated with some type of thrombosis, such as venous thromboembolism (VTE) or disseminated intravascular coagulation (DIC).. This retrospective study was designed to examine the frequency of thrombosis in 478 patients with malignant diseases in comparison to that observed in 121 patients without malignant diseases and to evaluate the efficacy of fibrin-related markers (FRMs), such as soluble fibrin, fibrinogen and fibrin degradation products and D-dimer, in diagnosing thrombosis.. The frequency of thrombosis, including 62 cases of VTE, 63 cases of DIC and nine cases of cerebrovascular thrombosis, was significantly higher in the patients with malignant diseases (28.0%) than in the patients without malignant diseases (12.5%). DIC was frequently detected in the patients with hepatic cell cancer and hematopoietic malignancy, while VTE was frequently observed in the patients with colon cancer, breast cancer and urinary tract cancer. The FRMs levels were significantly higher in the patients with thrombosis than in the patients without thrombosis. A receiver operating characteristic analysis showed these markers to be useful for diagnosing thrombosis.. Patients with malignant diseases have a high risk of thrombosis, and elevated FRMs levels are useful for diagnosing thrombosis in patients with malignant diseases.

Topics: Adult; Aged; Biomarkers, Tumor; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Follow-Up Studies; Humans; Incidence; Japan; Male; Middle Aged; Neoplasms; Retrospective Studies; Risk Factors; ROC Curve; Venous Thromboembolism

Metastasis is the cause of over 90% of all human cancer deaths. Early steps in the metastatic process include: the formation of new blood vessels, the initiation of epithelial-mesenchymal transition (EMT), and the mobilization of tumor cells into the circulation. There are ongoing efforts to replicate the physiological landscape of human tumor tissue using three-dimensional in vitro culture models; however, few systems are able to capture the full range of authentic, complex in vivo events such as neovascularization and intravasation. Here we introduce the Prevascularized Tumor (PVT) model to investigate early events of solid tumor progression. PVT spheroids are composed of endothelial and tumor cells, and are embedded in a fibrin matrix containing fibroblasts. The PVT model facilitates two mechanisms of vessel formation: robust sprouting angiogenesis into the matrix, and contiguous vascularization within the spheroid. Furthermore, the PVT model enables the intravasation of tumor cells that is enhanced under low oxygen conditions and is also dependent on the key EMT transcription factor Slug. The PVT model provides a significant advance in the mimicry of human tumors in vitro, and may improve investigation and targeting of events in the metastatic process.

Topics: Blotting, Western; Cell Line, Tumor; Endothelial Cells; Epithelial-Mesenchymal Transition; Fibrin; Humans; Hypoxia; In Vitro Techniques; Microscopy, Fluorescence; Neoplasms; Neovascularization, Pathologic; RNA, Small Interfering; Snail Family Transcription Factors; Transcription Factors

Fibrin formation from fibrinogen is a rare process in the healthy organism but is a pathological feature of thrombotic events, cancer and a wide range of inflammatory conditions. We have designed and constructed an antibody phage display library (containing 13 billion clones) for the selective recognition of the N-terminal peptide of fibrin alpha chain. The key structural feature for selective fibrin binding was a K94E mutation in the VH domain. From this library, an antibody was isolated (termed AP2), which recognizes the five N-terminal amino acids of fibrin with high affinity (Kd=44nM), but does not bind to fibrinogen. The AP2 antibody could be expressed in various formats (scFv, small immune protein and IgG) and inhibited fibrin clot formation in a concentration-dependent manner. Moreover, the AP2 antibody stained the fibrin-rich provisional stroma in solid tumors but did not exhibit any detectable staining toward normal tissues. Using a radioiodinated antibody preparation and quantitative biodistribution studies in tumor-bearing mice, AP2 was shown to selectively localize to fibrin-rich F9 murine teratocarcinomas, but not to SKRC-52 human kidney cancer xenografts. Collectively, the experiments indicate that the AP2 antibody recognizes fibrin in vitro and in vivo. The antibody may facilitate the development of fibrin-specific therapeutic agents.

Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Blood Coagulation; Cell Line, Tumor; Fibrin; Fibrinogen; Humans; Immunoglobulin G; Mice; Molecular Sequence Data; Mutation; Neoplasm Transplantation; Neoplasms; Peptide Library; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Surface Plasmon Resonance; Thrombosis

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

Cancer increases the risk of venous thromboembolism (VTE). Here, we investigated the contribution of microparticle (MP)-dependent procoagulant activity to the prothrombotic state in these patients. In 43 cancer patients without VTE at study entry and 22 healthy volunteers, markers of in vivo and MP-dependent coagulation were measured and patients were prospectively followed for six months for the development of VTE. Procoagulant activity of MPs was measured in vitro using a tissue factor (TF)-independent phospholipid dependent test, a factor Xa-generation assay with and without anti-TF, and a fibrin generation test (FGT) with and without anti-factor VII(a). Markers of in vivo coagulation activation and total number of MPs at baseline were significantly elevated in cancer patients compared to controls (F1+2 246 vs. 156 pM, thrombin-antithrombin complexes 4.1 vs. 3.0 mg/l, D-dimer 0.76 vs. 0.22 mg/l and 5.53 x 10⁶ vs. 3.37 x 10⁶ MPs/ml). Five patients (11.6%) developed VTE. Patients with VTE had comparable levels of coagulation activation markers and phospholipid-dependent MP procoagulant activity. However, median TF-mediated Xa-generation (0.82 vs. 0.21 pg/ml, p=0.016) and median VIIa-dependent FGT (13% vs. 0%, p=0.036) were higher in the VTE group compared with the non-VTE group. In this exploratory study the overall hypercoagulable state in cancer patients was not associated directly with the MP phospholipid-dependent procoagulant activity. However, in the patients who developed VTE within six months when compared to those who did not, an increased MP procoagulant activity was present already at baseline, suggesting this activity can be used to predict VTE.

Topics: Aged; Blood Coagulation Tests; Blood Platelets; Cell-Derived Microparticles; Factor VIIa; Factor Xa; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Phospholipids; Platelet Activation; Prognosis; Prospective Studies; Risk; Venous Thromboembolism

Angiogenesis is one of the major processes controlling growth and metastasis of tumors. Angiogenesis inhibitors have been targeted for the treatment of various cancers for more than 2 decades. We have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues. Our lead compound, SR16388, is a potent antiangiogenic agent with binding affinity to estrogen receptor-α (ER-α) and -β (ER-β) at the nanomolar range. This compound inhibited the proliferation of human microvascular endothelial cells (HMVEC) and various types of human cancer cells in vitro. SR16388 inhibited embryonic angiogenesis as measured in the chick chorioallantoic membrane (CAM) assay. The blood vessel density in the CAM was greatly reduced after the embryos were treated with 3 μg/CAM of SR16388 for 24 h. SR16388 at a dose of 2 μM prevented tube formation in Matrigel after HMVEC cells were treated for 8 h. In a modified Boyden chamber assay, SR16388 inhibited the migration of HMVECs by 80% at 500 nM. Using a novel in vivo Fibrin Z-chamber model, we demonstrated that SR16388 at a single daily oral dose of 3 mg/kg for 12 days significantly inhibited the granulation tissue (GT) thickness and the microvessel density of the GT as compared to control. More importantly, SR16388 down-regulated the pro-angiogenic transcription factors, hypoxia inducible factor 1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) in non-small cell lung cancer (NSCLC) cells. Together, these effects of SR16388 can lead to the reduction of vascularization and tumor growth in vivo.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Chickens; Down-Regulation; Endothelial Cells; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Fibrin; G1 Phase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Nude; Microvessels; Neoplasms; Neovascularization, Pathologic; Phosphorylation; Rats; Rats, Inbred F344; STAT3 Transcription Factor; Steroids

P-selectin and fibrin(ogen) have pivotal roles in the hematogenous dissemination of tumor cells. CD44 variant isoforms, CD44v, have been identified as the major functional P-selectin ligands and fibrin receptors on metastatic colon carcinoma cells. The molecular recognition of CD44v by fibrin mediates firm adhesion at low shear, whereas CD44v-P-selectin binding supports transient rolling interactions at elevated shear stresses and low site densities of P-selectin. We used single-molecule force spectroscopy to provide a molecular interpretation for these two distinct adhesion events. The CD44v-P-selectin bond has a longer unstressed equilibrium lifetime, a lower reactive compliance and a higher tensile strength relative to the CD44v-fibrin bond. These intrinsic differences confer the ability to the CD44v-P-selectin pair to mediate binding at higher shear stresses. Increasing the duration of receptor-ligand contact (2-200 milliseconds) did not affect the micromechanical properties of the CD44v-P-selectin bond, but it increased the tensile strength and the depth of the free energy barrier of the CD44v-fibrin bond and decreased its reactive compliance. This bond strengthening at longer interaction times might explain why CD44v binding to immobilized fibrin occurs at low shear. Single-molecule characterization of receptor-ligand binding can predict the shear-dependent adhesive interactions between cells and substrates observed both in vitro and in vivo.

Topics: Cell Line, Tumor; Fibrin; Humans; Hyaluronan Receptors; Microscopy, Atomic Force; Neoplasms; P-Selectin; Protein Binding; Shear Strength; Spectrum Analysis

Most patients with malignant diseases are frequently complicated with some type of thrombosis, such as disseminated intravascular coagulation (DIC) or deep vein thrombosis (DVT)/pulmonary embolism (PE).. The cohort and retrospective study was designed to examine the frequency of thrombosis in patients with malignant diseases and to evaluate the efficacy of D-dimer and soluble fibrin (SF) for the diagnosis of thrombosis.. The plasma concentrations of D-dimer and SF were measured in patients with malignant diseases suspected of having thrombosis. D-dimer and SF were measured using a latex aggregation assay.. Thrombosis was observed in 23.3% of the patients with malignant diseases. Disseminated intravascular coagulation was frequently observed in patients with hepatoma, and DVT/PE was frequently observed in patients with colon cancer, lung cancer, and uterine cancer. The plasma levels of D-dimer and SF were increased in malignant diseases, especially hepatoma. Plasma levels of D-dimer and SF were significantly higher in patients with thrombosis in comparison to patients without thrombosis. A receiver operating characteristic (ROC) analysis showed the D-dimer and SF levels to be useful in the diagnosis of thrombosis.. Elevated D-dimer and SF levels might indicate a high risk of thrombosis in patients with malignant disease; however, these assays still need to be standardized.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Neoplasms; Predictive Value of Tests; Pulmonary Embolism; Retrospective Studies; ROC Curve; Thrombophilia; Venous Thrombosis; Young Adult

Topics: Blood Coagulation; Factor XIII; Fibrin; Hemorrhage; Humans; Intraoperative Complications; Neoplasms; Perioperative Care; Thrombin

A peptide targeted contrast agent, CLT1-(Gd-DTPA), was synthesized for molecular imaging of fibronectin-fibrin complexes in tumor tissue with magnetic resonance imaging (MRI). The T(1) and T(2) relaxivities of CLT1-(Gd-DTPA) were 4.22 and 4.45 mM(-1) s(-1) at 3 T, respectively. The targeted contrast agent specifically bound to tumor tissue and resulted in significant tumor contrast enhancement at a dose of 0.1 mmol Gd/kg for at least 60 min in mice bearing HT-29 human colon carcinoma xenografts as shown in dynamic MR images. In contrast, a control nontargeted contrast agent, Gd(DTPA-BMA), was cleared rapidly with little tumor enhancement 60 min postinjection. Tumor enhancement with CLT1-(Gd-DTPA) was significantly reduced after coinjection with a 3-fold excess of free CLT1 peptide. The preliminary study has shown that CLT1-(Gd-DTPA) can specifically bind to the fibrin-fibronectin complexes in tumor tissues, resulting in significant tumor enhancement. The targeted contrast agent has a potential for cancer molecular imaging with MRI.

Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Contrast Media; Fibrin; Fibronectins; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Mice; Neoplasms; Peptides, Cyclic

Chicken fat clot (CFC), a fibrin-like substance, is sometimes found in the heart and large blood vessels in some autopsy cases. Reports of detailed histological findings of CFC are scant. We therefore examined CFC histologically in 53 autopsy cases and its correlation with ante-mortem or post-mortem evidence. We found three microscopic patterns of CFC: (1) wavelike fibrin fibers (WFF), (2) short fibrin fibers (SFF), and (3) short fibrin fibers mixed with wavelike fibrin fibers (SFF+WFF). WFF were found in the cases that survived less than 3 h after poisoning, burns, asphyxia, intracerebral hemorrhage, etc. SFF were found in the cases that survived more than 1 day after malignant neoplasms and acute or chronic inflammatory diseases, etc. SFF+WFF were found in the cases that died of inflammatory diseases, chronic heart failure, hemorrhagic shock, drowning, etc. About two-thirds of the SFF+WFF cases survived more than 1 day, with the rest surviving less than that. Our study confirmed three CFC patterns and their relation with survival interval. Therefore, these findings can be used as an index of the survival interval of a few acute and most chronic medico-legal death cases.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Female; Fibrin; Forensic Pathology; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasms; Respiratory Tract Diseases; Retrospective Studies; Survival Analysis; Thrombosis; Time Factors; Wounds and Injuries

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

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

Screening of a phage library for peptides that bind to clotted plasma in the presence of liquid plasma yielded two cyclic decapeptides, CGLIIQKNEC (CLT1) and CNAGESSKNC (CLT2). When injected intravenously into mice bearing various types of tumors, fluorescein-conjugated CLT peptides accumulated in a fibrillar meshwork in the extracellular compartment of the tumors, but were not detectable in other tissues of the tumor-bearing mice. The tumor homing of both peptides was strongly reduced after coinjection with unlabeled CLT2, indicating that the two peptides recognize the same binding site. The CLT peptide fluorescence colocalized with staining for fibrin(ogen) present in the extravascular compartment of tumors, but not in other tissues. The CLT peptides did not home to tumors grown in fibrinogen-null mice or in mice that lack plasma fibronectin. The CLT peptides also accumulated at the sites of injury in arteries, skeletal muscle, and skin. We conclude that the CLT peptides recognize fibrin-fibronectin complexes formed by clotting of plasma proteins that have leaked into the extravascular space in tumors and other lesions. These peptides may be useful in targeting diagnostic and therapeutic materials into tumors and injured tissues.

Topics: Animals; Blood Coagulation; Cell Line, Tumor; Fibrin; Fibronectins; Humans; Mice; Mice, Knockout; Neoplasms; Peptide Library; Peptides, Cyclic; Tissue Distribution; Wounds and Injuries

Fibrin-related markers such as soluble fibrin (SF) and D-dimer are considered useful for the diagnosis of thrombosis. However, the evidence for diagnosis of thrombosis by fibrin-related markers is not well-established.. To evaluate the cutoff values of D-dimer and SF in the diagnosis of thrombosis.. Plasma concentrations of SF and D-dimer were measured in 784 inpatients suspected of having thrombosis between 1 August 2003 and 31 December 2004, and then correlated with thrombosis.. Plasma concentrations of D-dimer and SF were significantly higher in patients with disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT) and cerebral thrombosis, compared with those in patients without thrombosis. When cutoff values of > 3.0 microg mL(-1) for D-dimer and > 6.0 microg mL(-1) for SF were used for the diagnosis, more than 50% of patients (with the exception of liver transplant patients and postoperative patients) had thrombosis. Receiver operating characteristic analysis showed that SF was more useful than D-dimer for the diagnosis of thrombosis (i.e. DVT and DIC). The cutoff value of D-dimer (7.87 microg mL(-1)) was the same for DVT and DIC, while that of SF was slightly lower for DVT (7.05 microg mL(-1)) than for DIC (8.60 microg mL(-1)). Our findings suggest that high levels of plasma fibrin-related markers reflect high risk for thrombosis.

Topics: Aged; Biomarkers; Bone Diseases; Communicable Diseases; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Intracranial Thrombosis; Male; Middle Aged; Neoplasms; Risk Factors; ROC Curve; Venous Thrombosis

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

The two-kringle domain of tissue-type plasminogen activator (t-PA) has previously been shown to contain anti-angiogenesis activity. In this study, we explored the potential in vivo anti-tumor effects of the recombinant kringle domain (TK1-2) of human t-PA. Anti-tumor effects of purified Pichia-driven TK1-2 were examined in nude mice models by subcutaneous implantation of human lung (A-549) and colon (DLD-1, HCT-116) cancer cell lines. Mice bearing the tumors were injected with PBS or purified TK1-2 (30 mg/kg) i.p. every day for 22 days. TK1-2 treatment suppressed the A-549, DLD-1, and HCT-116 tumor growth by 85.3%, 52.4%, and 62.5%, respectively. Immunohistological examination of the tumor tissues showed that TK1-2 treatment decreased the vessel density and also the expression of angiogenesis-related factors including angiogenin, VEGF, alpha-SMA, vWF, and TNF-alpha, and increased the apoptotic fraction of cells. TK1-2 neither inhibited in vitro growth of these cancer cells nor affected t-PA-mediated fibrin clot lysis. These results suggest that TK1-2 inhibits the tumor growth by suppression of angiogenesis without interfering with fibrinolysis.

Topics: Angiogenic Proteins; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Fibrin; Gene Expression Regulation, Neoplastic; Humans; Kringles; Male; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tissue Plasminogen Activator

This study investigated the connection among HER-2 gene amplification, HER-2 protein expression, and markers of tumor angiogenesis and oxygenation in patients with operable, invasive breast tumors.. From 1988 to 1995, 425 patients with metastatic breast cancer were enrolled in a study of high-dose chemotherapy with autologous transplant. Primary tumor blocks were obtained and evaluated using immunohistochemistry (IHC) staining of vessels with von Willebrand factor antibody. Mean microvessel densities (MVD) were determined by counting von Willebrand factor stained cells in three separate "vascular hot spots" using image analysis. Tumor samples were also stained for HER-2 by IHC, HER-2 gene amplification by fluorescence in situ hybridization, carbonic anhydrase 9 by IHC, and vascular endothelial growth factor (VEGF) by IHC. Plasma from 36 patients with primary tumor samples had VEGF (R&D Systems, MN) and d-dimer (American Diagnostica, Greenwich, CT) levels determined.. There was a significant positive correlation between HER-2 gene amplification and both maximum and average MVD (Spearman coefficient = 0.51 and 0.50; P = 0.03 and 0.05, respectively). There was an inverse correlation with HER-2 gene amplification and expression of the tumor hypoxia marker CA-9 (chi(2) P = 0.02). The level of HER-2 gene amplification correlated with plasma d-dimer levels (Spearman coefficient = 0.43; P = 0.021). Interestingly, tumors with HER-2 by IHC had decreased amounts of VEGF staining (chi(2) = 5.81; P = 0.01). There was no correlation between HER-2 by IHC and MVD or d-dimer. Of all of the variables examined, only average (P = 0.0016) and maximum MVD (P = 0.0128) predicted disease-free survival (Cox univariate model).. HER-2-amplified breast cancers have increased amounts of angiogenesis, decreased amounts of hypoxia, and increased markers of fibrin degradation. These findings have prognostic, predictive, and therapeutic implications in breast cancer treatment.

Topics: Breast Neoplasms; Carbonic Anhydrases; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Hypoxia; Immunohistochemistry; In Situ Hybridization, Fluorescence; Microcirculation; Neoplasms; Neovascularization, Pathologic; Oxygen; Prognosis; Receptor, ErbB-2; Time Factors; Vascular Endothelial Growth Factor A; von Willebrand Factor

Topics: Cell Division; Cell Size; Collagen Type I; Extracellular Matrix; Fibrin; Humans; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Neoplasms

The manuscript discussed in this preview describes that reconstituted three-dimensional extracellular matrices such as fibrillar collagen and fibrin exert stringent territorial growth control on cells. The authors show that tumor cells are able to escape the matrix-enforced growth control effect (entrapment) by pericellular proteolysis mediated by MT1-MMP, a membrane bound matrix metalloproteinase capable of directly cleaving both type I collagen and fibrin but not by other, soluble matrix metalloprotinases. These data convincingly demonstrate one way that tumor cells orchestrate proteolysis to invade surrounding tissues.

Topics: Animals; Cell Division; Collagen Type I; Fibrin; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Neoplasm Invasiveness; Neoplasms

The thrombin activatable fibrinolysis inhibitor (TAFI) influences the pathways regulating fibrin formation and deposition. The enormous TAFI plasma level variability present in adults may be explained by a combination of two polymorphisms in the TAFI gene (+1542C>G; 505G>A). We aimed to correlate these two polymorphisms with plasma TAFI antigen concentrations in healthy children and pediatric oncology patients with and without venous thrombosis who were supplied with Broviac central venous catheters. Polymorphisms were detected by restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction (PCR) amplification, whereas TAFI concentration was determined using a commercial enzyme-linked immunosorbent assay (ELISA). Samples from 57 controls and 67 pediatric patients (11 venous thrombotic complications) were studied. TAFI levels in healthy children and patients were not influenced by gender or age. Compared with the 505GG carriers (wild type), 505AA carriers as well as heterozygous 505GA carriers each exhibited significantly higher TAFI antigen concentrations. In contrast, the lowest TAFI levels were detected in homozygous carriers of the +1542GG polymorphism. A combination of the genotype 505AA (homozygous carrier) and +1542CC (wild type) was present in 13 probands and resulted in the highest TAFI levels. Although in oncologic patients the risk of thrombosis was markedly increased by the heterozygous factor V 1691G>A mutation, the two TAFI polymorphisms investigated exerted no thrombogenic influence.

Topics: Age Factors; Antigens; Child; Child, Preschool; Factor V; Female; Fibrin; Histone Acetyltransferases; Humans; Infant; Leukemia; Lymphoma, Non-Hodgkin; Male; Neoplasms; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Reference Values; TATA-Binding Protein Associated Factors; Transcription Factor TFIID

In order to prospectively evaluate the predictive value of coagulation markers such as the fibrin Ddimer for survival of cancer patients, we analyzed their role in a prospective study at a University Hospital Institute of Medical Oncology. 268 consecutive outpatients with cancer were included, 72 in remission and 196 with active disease. All cause mortality in relation to the marker levels was measured. 99/268 patients died during the observation period of 4,484 patient months (mean: 17 months). Patients with active disease had a significant, 1.5-5-fold increased marker concentration compared to patients in remission. When analyzed in quartiles, the data showed a lower than predicted death rate in the first quartile and a significantly elevated mortality in the fourth marker quartile. The odds ratio for death predicted by the fibrin monomer (FM) in the fourth vs. the first quartile was 4.1 (95% C.I.: 1.7-9.7) and p = 0.005 for the multivariate analysis of the markers. We conclude that a single determination of coagulation markers, particularly of TAT, FM, and Ddimer is sufficient to strongly predict survival in cancer patients over the following 1-3 years.

Topics: Antithrombin III; Biomarkers; Blood Coagulation; Case-Control Studies; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Male; Neoplasms; Odds Ratio; Peptide Hydrolases; Predictive Value of Tests; Prognosis; Prospective Studies; Survival Analysis; Survival Rate

We have previously shown that cancer patients with solid tumour disease have increased plasma levels of both the free and total forms of the coagulation inhibitor, tissue factor pathway inhibitor (TFPI), whereas patients with leukemia and related blood malignancies have levels within the normal range. We now report that also the median plasma levels of the Factor Xa (FXa)-TFPI complex were significantly higher in patients with solid tumours, compared to patients with haematological malignancy and healthy controls. There were significant positive correlations between the FXa-TFPI complex and total TFPI antigen (r=.47, P=.001) and TFPI activity (r=.33, P<.023). In plasma samples from patients with solid tumours, the ratio between the FXa-TFPI complex and free TFPI was 3.4 times higher than in patients with haematological malignancies. Increased levels of the FXa-TFPI complex in solid tumour disease may reflect both increased FXa generation and the increased TFPI concentration in the patients. It is speculated that high levels of the inhibitory FXa-TFPI complex in cancer patients may protect against microthrombosis and organ failure, which are relatively rare in cancer despite long-lasting hypercoagulation.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Hematologic Neoplasms; Hemostasis; Humans; Lipoproteins; Middle Aged; Neoplasms; Protein Binding

Directional migration of capillaries towards tumour implants is generally assumed to be regulated by chemotaxis. Preliminary evidence has also been presented for the existence of a reverse chemotactic signalling pathway, with capillaries attracting tumour cells via paracrine factors. By using a variety of endothelial cell types and tumour cell lines, this study has systematically investigated chemotaxis between endothelial cells and tumour cells in two- and three-dimensional systems. Checkerboard analysis revealed faint attraction of human umbilical vein endothelial cells (HUVECs), but not porcine aortic endothelial cells (PAECs), by tumour cells. In reverse, both PAECs and HUVECs potently induced chemotactic migration of tumour cells. Using a microcarrier-based fibrin gel assay, directional migration of endothelial cells towards tumour cells was not observed. In reverse, tumour cells were strongly attracted by endothelial cells. Identification of endothelium-derived chemotactic molecules may provide a valuable approach for the treatment of tumour metastasis.

Topics: Animals; Capillaries; Cell Communication; Cell Culture Techniques; Chemotaxis; Culture Media, Conditioned; Endothelium, Vascular; Fibrin; Glioblastoma; Humans; Melanoma; Microscopy, Phase-Contrast; Neoplasms; Neovascularization, Pathologic; Swine; Tumor Cells, Cultured

Cancer-related fibrin deposition and fibrinolysis were investigated by two-dimensional gel electrophoresis of human solid tumor and effusion specimen in addition to plasma samples. Fibrinogen gamma-chain dimer indicating fibrin deposition and plasmin-generated fibrinogen beta-chain fragments were identified in various solid tumor types by amino acid sequencing, mass spectrometry analysis and Western blotting. In tumor-associated effusions, these techniques allowed to observe plasmin-generated fragments of fibrinogen alpha, beta and gamma-chains in addition to elevated levels of acute-phase proteins. Similar observations were made in case of inflammation-associated effusions. No fibrin degradation product was observed in plasma samples, however, high amounts of fibrinogen gamma-chain dimer crosslinked by transglutaminase were detected in plasma from tumor patients, but not in plasma from controls and patients suffering acute infections and/or inflammations. This finding demonstrated that high transglutaminase activity may be associated with cancer. The presented data indicate that the amount of crosslinked fibrinogen gamma-chain dimer in plasma may correlate with tumor-associated fibrin deposition. The tumor-biological relevance of this potential marker protein is discussed.

Topics: Biomarkers, Tumor; Case-Control Studies; Cross-Linking Reagents; Dimerization; Electrophoresis, Gel, Two-Dimensional; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Neoplasm Proteins; Neoplasms; Pleural Effusion, Malignant; Proteome; Tissue Distribution

When granulocytes are stimulated under certain clinical conditions, elastase is released therefrom and digests fibrin(ogen) independently of the plasmin system, which may also be mobilized simultaneously. Thus, discrimination of these 2 systems becomes urgent for the diagnosis and treatment of the underlying diseases. Using as immunogen a 97-kd granulocyte-elastase digest of human fibrinogen, we raised an antibody IF-123 that specifically recognizes elastase digests of human fibrin(ogen). The 97-kd elastase fragment resembles plasmic fragment D(1), and the epitope of this antibody is located on the Aalpha (196-204) residue segment. This segment appears to be masked in fibrin(ogen) but exposed when the Aalpha Leu 204-Ile 205 peptide bond is cleaved by elastase. Cathepsin G concomitantly released from granulocytes failed to expose the epitope. By an enzyme immunoassay using IF-123 as the capture antibody, the elastase digests of fibrin(ogen) can be measured in plasma samples without interference by abundantly coexisting fibrinogen. Indeed, we found that the elastase digests were mostly elevated in patients with inflammation or malignant tumors, but remained in a normal range in patients with a benign gastrointestinal tract disease such as duodenal ulcer and polyps in the gallbladder or the colon. Like the plasmic D-dimer, the elastase digests predominantly consisted of the DD/E complex and DD/E-containing high-molecular weight derivatives apparently corresponding to the phase-3 plasmic digests of cross-linked fibrin. (Blood. 2000;95:1721-1728)

Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibody Affinity; Enzyme-Linked Immunosorbent Assay; Epitopes; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Gastrointestinal Diseases; Granulocytes; Humans; Inflammation; Leukocyte Elastase; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Neoplasms

It is well recognized that, in order for a wound to heal, the fibrin clot must be eliminated by fibrinolytic enzymes. In certain instances, however, fibrin is ineffectively degraded or even not degraded. For example, in pregnancy, the placenta contains a layer of fibrin (Nitabuck's layer) which presents as 'self' to the immune system. Similar situations have been observed in many solid tumors. A hypothesis is presented according to which tumor cells can escape detection and attack by the immune system in most cancer patients. The tumor dons a 'coat' of the host's own protein on its cell surface. The coat is composed of fibrin and of a polymeric form of human serum albumin (HSA) which, by contrast to pure fibrin, is resistant to fibrinolytic degradation. Such a coated tumor appears as 'self' to the immune system, and thus is not detected as a tumor by the immune system (i.e. natural killer cells). When tumors are prepared for in vitro assays against drugs, they are routinely treated with proteolytic enzymes (e.g. pepsin, or chymotrypsin, etc.) which dissolve the protein coat, exposing the tumor cell surface to the drug. Thus, the in vivo existence of a coat on the tumor surface may explain why some drugs have little or no effect in vivo, while the same drugs are active in vitro.

Topics: Albumins; Biopolymers; Cell Survival; Disulfides; Fibrin; Humans; Hydrolysis; Neoplasms

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

From a registry of 136 patients undergoing pericardiocentesis, 14 patients with autoimmune and 15 patients with neoplastic effusions were selected. All underwent pericardioscopy, epicardial and pericardial biopsy with histologic, immunohistologic, and polymerase chain reaction/or in situ hybridization analysis for microbial DNAs and RNA. Pericardioscopy identified neoplastic effusions by the high occurrence of protrusions. Fibrin threads and layers and neovascularization were found in both groups. For identification of the inflammatory and neoplastic process, the combined analysis of the cytology of the effusion and epicardial biopsy evaluation proved to be most important. Epicardial biopsy demonstrated a slightly higher sensitivity for identifying neoplastic disorders in the pericardium than cytology alone. Pericardial biopsy was inconclusive. Intrapericardial administration of 1 g of crystalloid triamcinolone in autoreactive pericarditis prevented recurrence in 13 of the 14 cases after 3 months and in 12 of the 14 cases after 1 year. In neoplastic effusion, intrapericardial administration of 50 mg cis-platin for 24 h prevented recurrence of a hemodynamically relevant effusion after 3 months in all, and after 6-12 months in 14 of 15 patients. Mortality in neoplastic effusion due to noncardiac tumor progression was 47 and 80%, respectively, after 3 and 6 months, as can be expected in endstage neoplastic disease. This pilot study demonstrates that local drug application is feasible, life-saving, and well tolerated by the patients. It opens perspectives for local drug application in other cardiac disorders as well.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Antineoplastic Agents; Autoimmune Diseases; Bacterial Infections; Biopsy; Cisplatin; Endoscopy; Female; Fibrin; Glucocorticoids; Humans; Male; Middle Aged; Neoplasms; Neovascularization, Pathologic; Paracentesis; Pericardial Effusion; Pericarditis; Pericardium; Pilot Projects; Sensitivity and Specificity; Survival Rate; Triamcinolone

Fibrin is found in most solid tumours, and there is speculation regarding its role in tumour invasion and metastasis. An assay to quantitate fibrin levels in tissues would be a useful preliminary tool in assessing the above. Such an assay to quantitatively detect levels of fibrin in various types of canine tumour was developed. This procedure involved an ELISA using a monoclonal antibody (MAb 1H10) for canine fibrin as a capture antibody and a polyclonal antibody to human fibrinogen conjugated to horseradish peroxidase as the detection antibody. The ELISA is calibrated against known concentrations of freeze-fractured fibrin derived from clotted dog plasma. The assay takes 3.5 hours, and concentrations as low as 0.1 microg fibrin per milliliter of solubilised tumour can be readily detected. ELISA dilution curves for fibrin from various types of canine tumour were found to be parallel to the standard canine fibrin calibration curve. The intraassay and interassay variabilities of the assay gave coefficients of variation in the range of 2.4-4.5% and 7.2-7.8%, respectively, for the calibrator standard, in a concentration range of 0.1-10 microg/ml. Using this assay, we reported the levels of fibrin in three different types of malignant canine tissue.

Topics: Animals; Antibody Specificity; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Freeze Fracturing; Hemangioma; Kidney Neoplasms; Male; Mammary Neoplasms, Animal; Neoplasms

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

Plasma-soluble fibrin monomer (SFM) level in patients with disseminated intravascular coagulation (DIC) was significantly higher than the level in patients with pre-DIC or in non-DIC patients, and the level in patients with pre-DIC was significantly higher than that in non-DIC patients. There was no significant difference in plasma SFM levels among various diseases underlying DIC. Plasma SFM level in patients with good outcome was significantly decreased after treatment for DIC. The sensitivity of fibrin degradation products and platelet number was high for DIC, but not for pre-DIC. The sensitivity of thrombin-antithrombin III complex, plasmin-plasmin inhibitor complex, and SFM was high for both DIC and pre-DIC. The specificity of these markers was also high. Receiver operating characteristic analysis suggests that plasma SFM level could be the most useful marker for the diagnosis of both DIC and pre-DIC.

Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Leukemia; Molecular Sequence Data; Neoplasms; Platelet Count; Prognosis; Retrospective Studies; Sensitivity and Specificity; Sepsis

Disseminated intravascular coagulation (DIC) is one of the most critical complications of malignant diseases. It is conventionally diagnosed by a decrease in platelets and an increase in fibrin/fibrinogen degradation products (FDP). Recently, an immunological assay was developed that can directly quantify the amount of soluble fibrin (SF) formed in the blood. This study examined this assay system in the diagnosis of DIC and found that it is a good indicator of both fibrin formation and of DIC. Plasma levels of SF correlated well with the DIC score, which is determined according to the 'DIC Scoring Guideline' proposed by the DIC Study Group under the Japanese Ministry of Public Welfare in 1988. It also correlated well with the serum levels of FDP. Normal values of plasma SF ranged between 0 and 9.50 micrograms/ml. Interestingly, values of SF in females tended to increase with age, for reasons that are not yet determined.

Topics: Adolescent; Adult; Aged; Antithrombin III; Child; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Humans; Leukemia; Lipids; Liver; Male; Middle Aged; Neoplasms; Peptide Fragments; Peptide Hydrolases; Prothrombin; Solubility

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

Despite increased concentration of plasminogen activators in malignant tumors, fibrinolytic potential in blood of cancer patients and tumor tissue is low. At the same time histochemical and microscopic examination revealed the presence of fibrin-like material coating tumor cells. It is postulated in the present paper that the increased concentrations of -SH groups and arginine-rich peptides, and the activation of tissue transglutaminases in the tumor tissue are responsible for the resistance of the fibrin coat to enzymatic degradation. The fibrin coat, in turn, causes neoplastic cells not to be recognized by the immunological system and thus makes them immune to the attack by the natural killer cells. Administration of naturally occurring, but diminished in cancer, derivatives of alpha ketoaldehydes resistant to glyoxalases, reverses the effect of -SH and arginine-rich peptides, and reactivates fibrinolysis. Consequently, removal of the fibrin coat from tumor cells makes them vulnerable to the attack of killer cells and their subsequent elimination.

Topics: Arginine; Fibrin; Fibrinolysis; Humans; Models, Biological; Neoplasms; Pyruvaldehyde; Sulfhydryl Compounds; Transglutaminases

The mean levels of fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT), and soluble fibrin (tPA method) in cancer patients (n = 32) were intermediate between those of patients with cerebral infarction and pancreatitis who had the most abnormal results and patients with myocardial infarction and pneumonia who had the least abnormal results. Patients with disseminated malignancies (n = 16) had significantly higher mean levels of FPA (10.6 vs. 5.3 nmol/l) and TAT (11.0 vs. 4.4 pmol/l) than patients with limited malignancies (n = 16). The difference in soluble fibrin (fibrin monomer, FM; 22.1 vs. 18.0 nmol/l) was not significant. The values of FPA, FM, and TAT in the patient population correlated significantly. There was a negative correlation between the level of antithrombin and test results for FPA (-0.69), FM (-0.48), and TAT (-0.38) in the cancer patients. Even cancer patients with locally limited disease may have elevated FPA, FM, and TAT test results, indicating a state of definite hypercoagulation.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antithrombin III; Blood Coagulation Disorders; Blood Coagulation Tests; Cerebral Infarction; Female; Fibrin; Fibrinopeptide A; Humans; Male; Middle Aged; Myocardial Infarction; Neoplasms; Pancreatitis; Peptide Hydrolases; Pneumonia; Predictive Value of Tests; Reference Values

Different coagulation and fibrinolysis parameters were investigated in 149 patients with metastatic and non-metastatic tumours and results were compared with those obtained in a healthy population. Results showed a significant increase of thrombin-antithrombin complexes, fibrinopeptide A (FPA) and fibrin monomers in the group of patients (p less than 0.001). There was also a significant prolongation of euglobulin lysis time (p less than 0.005) and an increase of plasminogen activator inhibitor activity (p less than 0.0001), fibrinogen degradation products (p less than 0.001), and D-dimer (p less than 0.05) in the group of patients as compared to controls; FPA levels were also increased in patients with metastases (p less than 0.005). This study demonstrates clotting activation, at the level of fibrinogen to fibrin conversion, and impairment of fibrinolysis in patients with malignancy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Fibrinopeptide A; Humans; Male; Middle Aged; Neoplasms; Tissue Plasminogen Activator

Despite the growing evidence implicating intratumoural fibrin formation in the progression of malignant tumours, the origin of coagulation factors that participate in extravascular clotting has not been elucidated. Using immunohistochemical methods we attempted to detect and localize clotting factors of extrinsic pathway in different human malignant tumours. Coagulation factors II, V, VII and X (FII, FV, FVII and FX) were detected in a huge number of cells showing spindle-shaped or stellate morphology. By double immunohistochemical labellings it was demonstrated that cells containing these clotting factors express monocyte/macrophage differentiation marker antigens recognized by Leu M3, Ki M7 and DAKO-macrophage monoclonal antibodies, i.e. they represent monocyte-derived, phagocytic tumour associated macrophages (TAMs). These findings suggest that TAMs can be viewed as clot cells, which in addition to the initiation of extravascular clotting by expressing procoagulant activity can also provide all the components necessary for the extrinsic thrombin formation.

Topics: Animals; Antigens, Surface; Blood Coagulation; Blood Coagulation Factors; Fibrin; Humans; Macrophages; Neoplasms; Rabbits

The clinical feature of rheumatoid arthritis (RA) is characterized by systemic-immunological, local-inflammatory phenomena. But it is the joint destruction which gives RA its dramatic course. Through the years we evaluated joint tissues of app. 14,500 patients with defined RA and besides the conventional inflammatory processes we could prove a mechanism which is responsible for the joint destruction and which is typical for RA. Following an exudative episode, compact, homogeneous cell masses can occur in the synovial membrane which consist of macronuclear, immature, synoviogenous cells. These masses can encroach on the adjacent structures of articular cartilage and subchondral bone which consequently enzymatically will be degraded and destroyed. Since these rapidly growing cell masses are avascular in their aggressive stage, they soon will collapse. The surviving cells "modulate" to fibroblast which start collagen synthesis and thus form the well-known pannus. In the area of the compact, homogeneous cell masses of synovial origin, there are no lymphocytes and plasma cells nor PMN or macrophages. Macrophages only occur after the breakdown of the cell masses and the beginning of pannus formation, this also is the case with lymphocytes and plasma cells. Thus, the immature synoviogenous cell masses are in contrast to the initial synovitis not of inflammatory character. Their cytological and aggressive behavior rather shows oncological analogies. This also corresponds to our proof of the expression of myc and ras to a high degree in the aggressive cell masses in RA.

Topics: Arthritis, Rheumatoid; Cell Division; Fibrin; Humans; Joints; Neoplasms; Synovial Fluid; Synovial Membrane

We have already reported in Balb C mouse transplantable mammary carcinoma, that uroporphyrin I and III are superior as tumour localizers when compared to hematoporphyrin derivative and a derivative thereof, photofrin II. This study compares the binding of porphyrins to proteins which may be found in tumour cells or stroma to investigate whether there is a common binding determinant. Coproporphyrin III and deuteroporphyrin IX which are non-tumour localizing porphyrins, were also part of the comparative study. The interaction of these porphyrins with acid soluble collagen and acid insoluble collagen, elastin, and fibrin was evaluated, and the binding of uroporphyrin isomers I and III and deuteroporphyrin IX to gelatin and fibrinogen, was also determined. The results suggest that collagen, especially the acid soluble form, and gelatin preferentially bind the four porphyrins which localize in mammary carcinoma tissue. The well reported observations that malignant epithelial cells, including breast cancer, produce collagen and contain a rate-limiting enzyme in collagen biosynthesis would support the notion that de novo synthesis of this protein may in part govern the tumour uptake and retention of porphyrins. Elastin, fibrinogen and fibrin showed non-discriminant binding to the porphyrins under study.

Topics: Animals; Cattle; Collagen; Elastin; Fibrin; Fibrinogen; Gelatin; Humans; In Vitro Techniques; Mice; Neoplasms; Porphyrins; Proteins

Soluble crosslinked fibrin derivatives (XDP) in serum were determined by enzyme immunoassay utilizing monoclonal antibodies and compared with serum fibrinogen/fibrin degradation products (FDP) assayed by conventional techniques. In healthy subjects and patients with miscellaneous disorders not usually associated with activation of the haemostasis mechanism, mean XDP levels were 45 and 70 ng/ml respectively. However, elevated levels of XDP occurred in conditions commonly associated with intravascular and possibly extravascular activation of the coagulation system. Markedly raised mean XDP values (677-6900 ng/ml) occurred in treated pulmonary embolism, disseminated neoplasia, severe inflammatory disorders and complicated postoperative states, and lesser but significant elevation (mean 150-400 ng/ml) in treated venous thrombosis, uneventful postsurgical states, localized neoplasia, liver disease and symptomatic arterial disease. Levels during initial streptokinase therapy (mean 24 000 ng/ml) fell tenfold as treatment was continued. The degree of XDP elevation over normal values was significantly higher than that of FDP in conditions with a propensity for venous thrombosis (post-operative states, disseminated neoplasia and inflammatory diseases) than in liver disease, localized neoplasia or patients receiving heparin therapy for venous thromboembolism.

Topics: Adult; Aged; Antibodies, Monoclonal; Blood Coagulation; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Immunoenzyme Techniques; Inflammation; Liver Diseases; Middle Aged; Neoplasms; Streptokinase; Thromboembolism; Vascular Diseases

Extravascular coagulation is a prominent feature of such important pathological processes as cellular immunity and neoplasia and has been thought to result from procoagulants associated with the inflammatory or tumor cells peculiar to these entities. It was found that increased microvascular permeability alone is sufficient to induce equivalent extravascular coagulation in several normal tissues. The results indicate that saturating levels of procoagulant are present even in normal tissues and that microvascular permeability is a rate-limiting step in extravascular coagulation.

Topics: Animals; Blood Coagulation; Bradykinin; Capillary Permeability; Fibrin; Fibrinogen; Guinea Pigs; Histamine; Neoplasms; Skin; Skin Physiological Phenomena

Alterations characteristic of the hypercoagulation syndrome such as changes in fibrinogen content, in FDP concentration and platelet counts as well as the presence of fibrinogen complexes were demonstrated by laboratory findings in 175 patients with severe diseases and disturbances of haemostasis. Twenty per cent of the patients showed no clinical signs of disturbances of haemostasis, in 32.5 per cent pronounced venous thrombosis occurred, bleeding complications arised in 28 per cent and microthrombosis developed in 20 per cent. The different findings in the individual groups are assumed to be due not only to haemostatic factors but also to other ones.

Topics: Blood Coagulation Tests; Cardiovascular Diseases; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Neoplasms; Partial Thromboplastin Time; Platelet Count; Postoperative Complications; Pregnancy; Pregnancy Complications, Hematologic; Thrombosis

Normal and established human epithelial cell lines obtained from the same organs were compared for their capacity to retract a fibrin clot. Fibrin clot retraction was maximal in normal epithelial cells, reduced in established nontumorigenic lines, and lost in tumorigenic cancer cell lines. Fibrin clot retraction efficiency seemed to be related to the degree of cellular spreading within the clot at the end of the test. Previous works and the present study suggest that fibrin clot retraction is correlated with some steps of cell transformation in vitro.

Topics: Cell Communication; Cell Count; Cell Line; Cell Transformation, Neoplastic; Clot Retraction; Epithelial Cells; Fibrin; Humans; Neoplasms

The expression of tissue factor activity was evaluated in homogenates and in intact whole cells from a variety of human and nonhuman cell lines of normal and neoplastic origin. A high degree of species specificity in the interaction of tissue factor with other coagulation factors was observed in guinea pig, rat, mouse, and hamster cells. Tissue factor was present in significant amounts in homogenates of both the normal and neoplastic cells tested in all four species examined. No correlation was observed between the amount of tissue factor detected in cell homogenates and the derivation of the cell line from normal versus neoplastic tissue. Intact cells also expressed tissue factor activity, but lower levels were found in most cell lines examined. The significance of these data is discussed with regard to fibrin deposition around tumors in vivo.

Topics: Animals; Brain Chemistry; Cell Line; Factor VII; Factor VIIa; Factor X; Fibrin; Guinea Pigs; Humans; Membrane Proteins; Mice; Neoplasms; Rats; Skin; Species Specificity; Thromboplastin

Topics: Blood Coagulation; Diagnosis, Differential; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Heparin; Humans; Labor, Obstetric; Neoplasms; Pregnancy; Purpura, Thrombotic Thrombocytopenic; Snake Bites; Thrombin

Topics: Adolescent; Adult; Cell Line; Cell Survival; Child; Clot Retraction; Embryo, Mammalian; Female; Fibrin; Fibroblasts; Humans; Infant, Newborn; Male; Neoplasms; Pregnancy; Skin; Skin Physiological Phenomena

Topics: Biocompatible Materials; Embolization, Therapeutic; Factor XIII; Fibrin; Humans; Neoplasms; Sutures; Thrombin

Topics: alpha-2-Antiplasmin; Fibrin; Fibrinolysin; Fibrinolysis; Hemostasis; Humans; Neoplasms; Plasminogen; Plasminogen Activators

Heparinized blood was taken up into capillary tubes and kept in vertical position at 37 degrees C for 24 hours to allow the red cells to sediment. Microclots appearing as radiant fibrin stars were seen under phase microscopy in the plasma portion of blood from certain patients. Such a positive microclot generation (MCG) test occurred in patients with some inflammatory diseases and cancer as well as in patients with certain skin disorders. The data suggest that the MCG test may serve in the detection of endotoxemia.

Topics: Blood Sedimentation; Crystallization; Endotoxins; Female; Fibrin; Humans; Inflammation; Male; Neoplasms; Pregnancy; Skin Diseases

Radiation-induced liver disease is characterized structurally by progressive fibrous obliteration of central veins (veno-occlusive disease [VOD]). The pathogenesis is unknown. Samples of liver from 11 patients with radiation-induced VOD were studied by light and electron microscopy for evidence of central vein thrombosis. The patients had received fractionated radiation with total doses of 1,850 to 4,050 rads, or single doses of 1,000 rads. In addition, six patients had received chemotherapy. Although usually undetectable by light microscopy, fibrin was found in all samples, sometimes in large amounts, within central veins, and also often in the adjacent sinusoids. One sample had a small platelet aggregate. In two patients, portal veins also showed occlusive lesions. We postulate that ionizing radiation injures preferentially the endothelial cells of central veins, which leads to focal deposition of fibrin. The resulting fibrin network is eventually replaced by collagen, causing fibrous occlusion. In several patients, this type of liver injury occurred at radiation doses conventionally considered safe even in the absence of chemotherapy.

Topics: Adolescent; Adult; Aged; Budd-Chiari Syndrome; Female; Fibrin; Hepatic Veins; Humans; Liver; Male; Middle Aged; Neoplasms; Radiation Injuries; Radiotherapy

Topics: Adult; Afibrinogenemia; Aged; Animals; Carcinoma; Factor XIII Deficiency; Fibrin; Humans; Middle Aged; Neoplasms; Neoplasms, Experimental; Rats; Sulfhydryl Compounds

Highly purified fibrinogen-fibrin related antigen (FR-antigen) was isolated with good recovery from 1.0--2.0 ml of human plasma, by immuno-affinity chromatography with antibody specific for fibrinogen and fibrin, and plasmin degradation products X, Y, D and D-D dimer. In FR-antigen from defibrinating patients there was evidence for thrombin activity alone (mainly disseminated cancer) or both plasmin and thrombin (mainly abruptio placentae). Thus, the molar ratio of N-terminal Gly-Tyr in the FR-antigen of 18 of 20 patients strongly suggested thrombin activity (95th percentile). In addition, sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) on unreduced samples frequently showed bands similar in mol wt to fragments X, Y and D, and in the reduced samples A alpha and B beta chain degradation, both indicating plasmin activity. 'N-terminal beta chain Ala' was elevated in the antigen of four of 20 patients, also suggesting plasmin activity (99th percentile). Combined thrombin, plasmin and factor-XIII activity, as shown with high levels of serum FR-antigen (greater than 10 mg/dl). In some defibrinating patients, especially those with disseminated cancer, heterogeneity of unreduced FR-antigen and A alpha chain degradation, both indicators of mild plasmin-like activity which are commonly seen in normals, were absent.

Topics: Abruptio Placentae; Amino Acids; Antigens; Chromatography, Affinity; Electrophoresis, Polyacrylamide Gel; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Male; Neoplasms; Pregnancy

The binding of two tumor localizing porphyrins, meso-tetra (4-carboxyphenyl) porphine (TCPP) and meso-tetra (4-sulfonatophenyl) porphine (TPPS4) to fibrin clots was determined in vitro. Both TCPP and TPPS4 were found to bind extensively, although weakly, to fibrin. No appreciable binding by Hematoporphyrin IX to the fibrin matrix was detectable. Similar results were obtained whether the clot was non-crosslinked or crosslinked with factor XIII. Photoirradiation of a porphyrin-impregnated non-crosslinked clot rendered it urea insoluble. Electrophoretic analysis indicated that the alpha chain of the fibrinogen molecule was most affected by photoirradiation. This was manifested as a loss of the alpha chain intensity and a concomitant increase of high molecular weight components, suggesting the formation of crosslinks. No substantial differences were noted in susceptibility to plasmin lysis between photoirradiated and non-irradiated clots. Photoirradiated clots were, however, significantly more resistant to lysis induced by the plasminogen activators urokinase and streptokinase, suggesting that inactivation of plasminogen within the clot matrix had occurred during photoirradiation. The relevance of porphyrin binding to fibrin with regard to tumor localization and destruction is also discussed.

Topics: Binding Sites; Electrophoresis, Polyacrylamide Gel; Fibrin; Fibrinolysis; Humans; Light; Neoplasms; Photochemotherapy; Porphyrins; Streptokinase; Urokinase-Type Plasminogen Activator

Topics: Binding Sites; Cell Membrane; Cell Transformation, Viral; Cells, Cultured; Fibrin; Fibrinogen; Fibroblasts; Fibronectins; Fluorescent Antibody Technique; Humans; Immune Sera; In Vitro Techniques; Neoplasms; Protein Binding; Receptors, Drug; Simian virus 40

The interaction of hematoporphyrin IX and two synthetic porphyrin tumor localizers, meso-tetra (4-carboxyphenyl) porphine (TCPP) and mesotetra (4-sulfonatophenyl) porphine (TPPS4) with fibrinogen was investigated in the presence and absence of light. Both TPPS4 and TCPP were found to bind to fibrinogen in greater than a 1/1 mole ratio in the absence of light. Chromatographic analysis indicated that during illumination TPP4 bound to fibrinogen to a greater extent that did either TCPP or hematoporphyrin. Both TCPP and TPPS4 were found to exhibit a greater inhibitory effect on clotting in the presence of light than did hematoporphyrin. In the absence of light and added Ca2+, both TCPP and TPPS4 were found to stimulate clotting at very specific porphyrin/fibrinogen concentration ratios, with TPPS4 being the more potent stimulator of the two. Hematoporphyrin exhibited little or no effect on clotting times. Fibrinogen, photoirradiated in the presence of the porphyrins was found to inhibit the clotting of unirradiated fibrinogen. A comparison of the stimulatory effects on clotting times by either calcium or TCPP and TPPS4 indicated that the porphyrins were capable of eliciting a greater stimulatory response than did calcium. The magnitude of the stimulatory response caused by the porphyrins alone was substantially reduced in the presence of calcium although the overall stimulatory response was increased but not additive. This suggests some interaction between either the calcium and porphyrin molecules or similarities in the respective stimulatory mechanism(s) involved. A possible correlation between these observations and the porphyrins ability to localize in tumors is also discussed.

Topics: Blood Coagulation; Fibrin; Fibrinogen; Humans; Neoplasms; Porphyrins; Time Factors; Whole Blood Coagulation Time

Topics: Collagen; Connective Tissue; Extracellular Space; Fetus; Fibrin; Fibronectins; Histocytochemistry; Humans; Kidney Diseases; Neoplasms; Reticulin; Tissue Distribution

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

Plasma fibronectin (cold-insoluble globulin) is known to be cross-linked to fibrin during the final stage of blood coagulation and is probably the major nonspecific opsonin of blood. We measured the concentration of plasma fibronectin in 36 hospitalized patients (11 with malignancy, 12 with infection, 13 with other underlying diseases) with evidence of fibrin depostion and lysis. Plasma fibronectin concentration was greater than 2 S.D. below the mean of normals in 17 of the patients (p less than 0.001). Depression of fibronectin was not related to severity of disseminated intravascular coagulation, as assessed by fibrinogen concentration and the quantity of FDP in serum. Depressed plasma fibronectin concentration and the quantity of FDP in serum. Depressed plasma fibronectin concentration was an unfavorable prognostic finding, inasmuch as 12 of the 17 patients with depressed fibronectin concentrations died during hospitalization as compared to five of the 19 patients with normal fibronectin concentrations (p less than 0.02). We speculate that specific depletion of plasma fibronectin, because of codeposition with fibrin or due to increased utilization as a nonspecific opsonin, may contribute to the organ failure seen in severely ill patients.

Topics: Adult; Bacterial Infections; Cold Temperature; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Glycoproteins; Humans; Male; Membrane Proteins; Middle Aged; Neoplasms; Virus Diseases

Topics: Animals; Chick Embryo; Collagen; Fibrin; Fibrinolysis; Humans; Neoplasms; Peptide Hydrolases; Virus Replication

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

The early demonstration of immunologic specificity of antibodies and the discovery of tumor antigenic specificity are reviewed in the light of experimental and clinical attempts to use such reagents in the management of cancer. Recent results in regard to tumor antigens and radiolabeled antibody preparations are shown to be practical for experimental diagnosis and therapy and potentially for similar clinical purposes.

Topics: alpha-Fetoproteins; Animals; Antibodies, Neoplasm; Antigens, Neoplasm; Carcinoembryonic Antigen; Colonic Neoplasms; Europe; Female; Fibrin; Hodgkin Disease; Humans; Immunization, Passive; Immunoglobulin G; Immunotherapy; Iodine Radioisotopes; Isotope Labeling; Male; Mice; Neoplasm Transplantation; Neoplasms; Ovarian Neoplasms; Rabbits; Radionuclide Imaging; Rats; Transplantation, Heterologous; United States

Topics: Aged; Arthritis, Rheumatoid; Blood Cell Count; Blood Platelets; Carbon Radioisotopes; Collagen Diseases; Factor XIII; Female; Fibrin; Fibrinolysis; Heart Failure; Humans; Hypertension, Malignant; Infections; Leukemia; Liver Diseases; Neoplasms; Pulmonary Embolism; Sepsis; Streptokinase

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: Blood Coagulation Factors; Brain; Cell Biology; Cell Survival; Fibrin; In Vitro Techniques; Iodine Radioisotopes; Neoplasms; Radiation Effects; Thromboplastin; Tissue Extracts

Topics: Animals; Capillary Permeability; Clone Cells; Education, Medical, Graduate; Epithelial Cells; Epithelium; Fibrin; Humans; Hypoxia; Intestinal Mucosa; Mice; Necrosis; Neoplasms; Radiation Dosage; Radiation Effects; Radiation Injuries, Experimental; Radiobiology; Radiology; Radiotherapy; Rats; Research; Serum Albumin, Radio-Iodinated; United Kingdom

Topics: Birefringence; Cell Division; Culture Techniques; Electric Stimulation; Fibrin; Neoplasms

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: Fibrin; Humans; Microscopy, Electron; Neoplasms

Topics: Breast Neoplasms; Colonic Neoplasms; Esophageal Neoplasms; Fibrin; Fibrinogen; Fibrinolysis; Gallbladder Neoplasms; Humans; Lymphatic Metastasis; Neoplasms; Pancreatic Neoplasms; Rectal Neoplasms; Stomach Neoplasms

Topics: Agglutination Tests; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Hemagglutination Inhibition Tests; Humans; Liver Cirrhosis; Neoplasms; Staphylococcus

Topics: Arginine; Fibrin; Fibrinogen; Fibrinolysis; Humans; Neoplasm Proteins; Neoplasms; Protein Binding

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

Topics: Adolescent; Female; Fibrin; Humans; Neoplasms; Ovarian Neoplasms; Sertoli-Leydig Cell Tumor

Topics: Animals; Blood Coagulation Tests; Ethanol; Evaluation Studies as Topic; Female; Fibrin; Fibrinogen; Hematologic Diseases; Humans; Kidney Diseases; Liver Diseases; Male; Neoplasms; Peptide Hydrolases; Postoperative Complications; Postpartum Period; Pregnancy; Protamines; Snakes; Thrombin; Venoms

Topics: Adolescent; Adult; Angina Pectoris; Chronic Disease; Diabetes Mellitus; Female; Fibrin; Fibrinogen; Hematologic Diseases; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Myocardial Infarction; Neoplasms

A rapid slide test for the detection of degradation products of fibrinogen/fibrin (FDP) using a new antibody-coated latex particle is described. The latex particle has been specifically coated with antibody to fragments D and E. The latex agglutination test (Thrombo-Wellcotest) has been compared with the tanned red cell haemagglutination inhibition immunoassay (TRCHII) in 143 patients with a variety of clinical conditions. There is a high degree of agreement between the methods with a coefficient of correlation of 0.83. The method provides a rapid, simple screening test for fibrin degradation products.

Topics: Antibodies; Fibrin; Fibrinogen; Hemagglutination Inhibition Tests; Humans; Hyperthyroidism; Kidney Diseases; Latex; Liver Diseases; Methods; Microspheres; Neoplasms; Pulmonary Embolism

Counterelectrophoresis using a discontinuous buffer system permits detection of fibrinogen-fibrin degradation products (FDP) under a variety of clinical circumstances. The method is sensitive, reliable, and is easily performed using conventional equipment in any clinical laboratory assuming the responsibility for assaying fibrinogen-fibrin degradation products.

Topics: Blood Coagulation Tests; Contraceptives, Oral; Female; Fibrin; Fibrinogen; Humans; Immunoelectrophoresis; Liver Cirrhosis; Methods; Neoplasms; Postoperative Complications; Precipitin Tests; Sepsis; Thrombin

Topics: Abruptio Placentae; Antigens; Blood Coagulation; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Humans; Liver Cirrhosis; Neoplasms; Pregnancy

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

Topics: Abortion, Septic; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Ethanol; Female; Fibrin; Hematoma; Humans; Leukemia; Liver Cirrhosis; Methods; Neoplasms; Phlebitis; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Sepsis

Topics: Adult; Agglutination Tests; Arthritis, Rheumatoid; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Contraceptives, Oral; Erythrocytes; False Negative Reactions; False Positive Reactions; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Hemagglutination Inhibition Tests; Hodgkin Disease; Humans; Immunoassay; Immunodiffusion; Kidney Diseases; Liver Cirrhosis; Lymphoma, Non-Hodgkin; Male; Methods; Middle Aged; Myocardial Infarction; Neoplasms; Plasminogen; Staphylococcus

Topics: Animals; Ascitic Fluid; Bordetella; Chloroform; Chromatography, Gel; Fibrin; Immunoelectrophoresis; Immunoglobulin G; Neoplasms; Proteins; Rabbits; Rats

Topics: Animals; Fibrin; Hospitals; Humans; Ireland; Neoplasms; Neoplasms, Experimental; Research; Thrombin; Thromboplastin

Topics: Adolescent; Adult; Age Factors; Aged; Animals; Anticoagulants; Arthritis, Rheumatoid; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Cardiovascular Diseases; Cattle; Child; Child, Preschool; Dogs; Electrophoresis; Female; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Hemorrhage; Hemorrhagic Disorders; Humans; Infant; Male; Menstruation; Methods; Middle Aged; Neoplasms; Plasminogen; Pregnancy; Rabbits; Sex Factors; Thromboembolism; Thrombosis; Uremia

Topics: Adenocarcinoma; Adenoma; Adrenal Gland Neoplasms; Breast Diseases; Breast Neoplasms; Female; Fibrin; Fluorescent Antibody Technique; Genital Neoplasms, Female; Hodgkin Disease; Humans; Lymph Nodes; Lymphatic Diseases; Melanoma; Methods; Neoplasms; Neoplasms, Nerve Tissue; Ovarian Neoplasms; Sarcoma; Stomach Neoplasms; Thyroid Neoplasms; Tuberculosis

Topics: Animals; Blood Coagulation Disorders; Blood Platelets; Busulfan; Fibrin; Fibrinogen; Hemolysis; Injections, Intravenous; Kidney Glomerulus; Models, Biological; Neoplasms; Platelet Adhesiveness; Purpura; Rabbits; Sepsis; Shock; Shwartzman Phenomenon; Sulfonic Acids; Thrombocytopenia

Topics: Biological Assay; Biopsy; Culture Media; Culture Techniques; Fibrin; Fibrin Foam; Methods; Neoplasms; Prognosis

Topics: Biological Assay; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelet Disorders; Female; Fibrin; Humans; Immunoelectrophoresis; Male; Neoplasms; Thrombin; Thrombocytopenia; Thromboplastin

Topics: Aminocaproates; Aprotinin; Cellulose; Chromatography; Chromatography, Gel; Fibrin; Fibrinogen; Hematologic Diseases; Humans; Immunoelectrophoresis; Liver Diseases; Macroglobulins; Neoplasms; Plasminogen; Streptokinase; Thrombin; Thrombosis

Topics: Blood Coagulation Disorders; Fibrin; Fibrinolysis; Heparin; Humans; Leukemia; Neoplasms; Thrombosis

Topics: Blood Coagulation; Blood Coagulation Factors; Fibrin; Humans; Neoplasms; Prothrombin

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: Cell Nucleus; Cytoplasm; Extraembryonic Membranes; Fibrin; Humans; Metabolism; Microsomes; Mitochondria; Neoplasms; Nitrogen; Phosphorus; Research; Thromboplastin

Topics: Enzymes; Fibrin; Humans; In Vitro Techniques; Neoplasms

Topics: Aged; Ascites; Breast; Breast Neoplasms; Cell Division; Culture Techniques; Epithelium; Female; Fibrin; Humans; Middle Aged; Neoplasms; Nylons; Ovarian Neoplasms; Pleura; Rectal Neoplasms

Topics: Animals; Antibodies; Brain Neoplasms; Fibrin; Humans; Iodine Isotopes; Neoplasms; Rabbits; Radioisotopes; Radionuclide Imaging

Topics: Alpha-Globulins; Anemia; Biological Assay; Biomedical Research; Blood Coagulation; Blood Coagulation Factors; Calcium; Collagen Diseases; Cysteine; Factor XIII; Fibrin; Hemorrhagic Disorders; Humans; Leukemia; Liver; Liver Diseases; Lymphoma; Neoplasms; Pathology; Serum Globulins; Sulfhydryl Compounds; Thrombin

Topics: Asparagine; Fibrin; Folic Acid; Immune Sera; Mast Cells; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Serine; Thrombin; Tissue Culture Techniques

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

Topics: Fibrin; Fibrin Foam; Humans; Neoplasms; Neoplasms, Radiation-Induced; Radiation Injuries; Radiodermatitis; Research; Skin Neoplasms

Topics: Fibrin; Humans; Neoplasms; Radioactivity; Radioisotopes

Topics: Amino Acids; Antibodies; Caproates; Fibrin; Iodine Isotopes; Neoplasms; Physiological Phenomena

Topics: Antibodies; Fibrin; Fibroma; Iodine; Iodine Isotopes; Myxoma; Neoplasms; Neoplasms, Experimental; Radioisotopes; Radiometry

Topics: Animals; Ascites; Carcinoma, Ehrlich Tumor; Fibrin; Fibrinolysis; Globulins; Mice; Neoplasms; Neoplasms, Experimental; Physiology; Research

Topics: Antibodies; Fibrin; Fibrinogen; Humans; Immunoglobulins; Iodine; Iodine Isotopes; Neoplasms

Topics: Brain Neoplasms; Diagnosis, Differential; Fibrin; Humans; Neoplasms

Topics: Antibodies; Fibrin; Humans; Neoplasms; Radiation; Radioisotopes

Topics: Fibrin; Humans; Neoplasms

Topics: Antibodies; Fibrin; Humans; Iodine; Iodine Radioisotopes; Neoplasms; Radioisotopes; Therapies, Investigational

Topics: Animals; Fibrin; Fibrinogen; Lymphoma, Non-Hodgkin; Neoplasm Transplantation; Neoplasms; Rats

Topics: Animals; Antibodies; Fibrin; Immunoglobulins; Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms; Rats

Topics: Fibrin; Fibrinolysis; Hematologic Diseases; Humans; Neoplasms

Topics: Animals; Connective Tissue; Fibrin; Humans; Neoplasms; Neoplasms, Connective Tissue; Spleen

Topics: Early Detection of Cancer; Early Diagnosis; Fibrin; Humans; Neoplasms

Topics: Blood Cells; Fibrin; Hodgkin Disease; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neoplasms; Sarcoma

Topics: Female; Fibrin; Fibrinolysis; Humans; Leiomyoma; Neoplasms; Uterine Neoplasms

Topics: Animals; Fibrin; Humans; Lesser Pelvis; Neoplasms; Pelvic Neoplasms; Porifera

Topics: Fibrin; Neoplasms; Proteolysis

Topics: Bronchi; Bronchial Neoplasms; Carcinoma, Bronchogenic; Fibrin; Humans; Lung Diseases; Neoplasms; Pneumonia

Topics: Abscess; Fibrin; Humans; Lung; Lung Abscess; Lung Neoplasms; Neoplasms

Topics: Fibrin; Fibrinolysis; Humans; Lymph Nodes; Neoplasms; Research; Tuberculosis; Tuberculosis, Lymph Node

Topics: Fibrin; Fibrinolysis; Hemorrhage; Humans; Male; Neoplasms; Prostatic Neoplasms; Syndrome

Topics: Fibrin; Fibrinolysis; Hemorrhagic Disorders; Humans; Male; Neoplasms; Prostatic Neoplasms

Topics: Cervix Uteri; Female; Fibrin; Humans; Inorganic Chemicals; Neoplasms; Wounds and Injuries

Topics: Antifibrinolytic Agents; Body Fluids; Enzyme Precursors; Female; Fibrin; Fibrinogen; Fibrinolysin; Hematologic Diseases; Humans; Neoplasms; Plasminogen; Pregnancy; Thrombolytic Therapy; Urine

Topics: Fibrin; Fibrinolysis; Leukemia; Lymphoma; Neoplasms

Topics: Abortion, Induced; Abortion, Spontaneous; Blood; Female; Fibrin; Fibrinolysis; Genital Diseases, Female; Gynecology; Humans; Neoplasms; Obstetrics; Pregnancy; Uterine Neoplasms; Uterus