fibrin and Liver-Neoplasms

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

Fibrinogen-like protein 2 (FGL2), which directly generates thrombin from prothrombin without activation of the conventional coagulation cascade, was shown to be overexpressed in various human malignant tumours.. Herein, we aimed to investigate its expression pattern, biological function and mechanism of action in hepatocellular carcinoma (HCC).. FGL2 expression and colocalization with fibrin was examined in 15 HCC tissues. FGL2 downregulation was performed by targeting microRNA in a HCCLM6 cell line in which FGL2 was highly expressed in xenografts of nude mice. The effects of FGL2 knockdown on tumour growth and angiogenesis were evaluated in vitro and in vivo. Cytometric bead arrays were employed to identify FGL2-regulated signalling pathways.. FGL2 was overexpressed in HCC tissues and colocalized with fibrin deposition. Knockdown of FGL2 expression in HCCLM6 cells (hFGL2(low) HCCLM6) resulted in delayed xenografts tumour growth within an observation period of 42 days and decreased vascularization, which was accompanied by decreased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In vitro hFGL2(low) HCCLM6 cells exhibited decreased proliferation without significant induction of apoptosis. Overexpression of FGL2 in HCCLM6 cells or addition of recombinant hFGL2 protein induced phosphorylation of p38-MAPK and ERK1/2 involving protease-activated receptors (PARs).activation.. FGL2 contributes to HCC tumour growth and angiogenesis in a thrombin-dependent manner, and downregulation of its expression might be of therapeutic significance in HCC.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Fibrin; Fibrinogen; Flow Cytometry; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Liver Neoplasms; Mice; Mice, Nude; MicroRNAs; Neovascularization, Pathologic; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thromboplastin

Vascular invasion is an important diagnostic and prognostic feature of hepatocellular carcinoma (HCC) in cirrhosis. Intravascular free-floating tumor clusters (IvCs) of HCC are found histologically in the vicinity of HCC. Thrombus formation is not seen morphologically in association with these IvCs, which are usually covered by endothelium.. Our hypothesis is that these IvCs are the result of a nondestructive form of vascular invasion by HCC, and we tried to define this aspect of microvascular invasion more accurately.. Tissue sections were stained with hematoxylin-eosin, and consecutive sections were stained for fibrin (Martius scarlet blue, fibrinogen), platelets (factor XIIIa), smooth muscle actin, and endothelium (CD34). We studied cirrhotic livers removed at transplantation between 1997 and 1999. Of the livers studied, 35 of 81 consecutive cirrhotic livers contained HCC, and 17 showed microscopic vascular invasion. Five of these 17 cases showed IvCs and were subjected to the study.. Presence or absence of thrombus formation in association with IvC.. Usually, IvCs were covered by endothelium, and no associated thrombus formation was seen. In 1 case of HCC, thrombus formation was seen focally in association with disruption of the endothelial coating.. We propose that the endothelial-lined trabecular structure of HCC everts, frondlike, via vascular structures within the tumor capsule into peritumoral vascular lumens without destruction of the endothelial coating. This may protect these HCC tumor projections from thrombus formation but may also act as a barrier to tumor extravasation, and this may be exploited from a therapeutic point of view.

Topics: Actins; Adult; Biomarkers, Tumor; Carcinoma, Hepatocellular; Endothelium, Vascular; Factor XIIIa; Female; Fibrin; Fibrinogen; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplastic Cells, Circulating; Receptors, Complement 3b

Although angiogenesis is a prerequisite for the growth of most human solid tumours, alternative mechanisms of vascularisation can be adopted. We have previously described a non-angiogenic growth pattern in liver metastases of colorectal adenocarcinomas (CRC) in which tumour cells replace hepatocytes at the tumour-liver interface, preserving the liver architecture and co-opting the sinusoidal blood vessels. The aim of this study was to determine whether this replacement pattern occurs during liver metastasis of breast adenocarcinomas (BC) and whether the lack of an angiogenic switch in such metastases is due to the absence of hypoxia and subsequent vascular fibrinogen leakage. The growth pattern of 45 BC liver metastases and 28 CRC liver metastases (73 consecutive patients) was assessed on haematoxylin- and eosin-stained tissue sections. The majority of the BC liver metastases had a replacement growth pattern (96%), in contrast to only 32% of the CRC metastases (P<0.0001). The median carbonic anhydrase 9 (CA9) expression (M75 antibody), as a marker of hypoxia, (intensity x % of stained tumour cells) was 0 in the BC metastases and 53 in the CRC metastases (P<0.0001). There was CA9 expression at the tumour-liver interface in only 16% of the BC liver metastases vs 54% of the CRC metastases (P=0.002). There was fibrin (T2G1 antibody) at the tumour-liver interface in only 21% of the BC metastases vs 56% of the CRC metastases (P=0.04). The median macrophage count (Chalkley morphometry; KP-1 anti-CD68 antibody) at the interface was 4.3 and 7.5, respectively (P<0.0001). Carbonic anhydrase 9 score and macrophage count were positively correlated (r=0.42; P=0.002) in all metastases. Glandular differentiation was less in the BC liver metastases: 80% had less than 10% gland formation vs only 7% of the CRC metastases (P<0.0001). The liver is a densely vascularised organ and can host metastases that exploit this environment by replacing the hepatocytes and co-opting the vasculature. Our findings confirm that a non-angiogenic pattern of liver metastasis indeed occurs in BC, that this pattern of replacement growth is even more prevalent than in CRC, and that the process induces neither hypoxia nor vascular leakage.

Topics: Adenocarcinoma; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Breast Neoplasms; Carbonic Anhydrases; Cell Hypoxia; Colorectal Neoplasms; Fibrin; Glycoproteins; Humans; Immunohistochemistry; Liver Neoplasms; Macrophages; Neovascularization, Pathologic; Vesicular Transport Proteins

Fibrin formation and removal occurs continuously during the development of malignancy. Moreover, plasma D-dimer is indicative of ongoing fibrinolysis, and soluble fibrin polymer (Thrombus precursor protein, TpP) represents thrombogenic activity. We evaluated the relationship between the levels of plasma D-dimer and TpP and tumor thrombosis in patients with hepatocellular carcinoma (HCC), and examined these markers as possible predictors of tumor thrombus in the portal or the hepatic vein.. Plasma levels of D-dimer and TpP were measured in 66 HCC patients (38 without tumor thrombosis, 28 with tumor thrombosis) and 29 healthy controls, by enzyme immunoassay using an Asserachrom D-Di kit (Diagnostica Stago, France) and a TpP kit (American Biogenetic Sciences, USA).. The plasma levels of D-dimer and TpP in HCC patients were found to be significantly higher than those in healthy controls, and these values were also significantly higher in patients with tumor thrombosis than those without tumor thrombosis. Positive D-dimer (>367 ng/ml) correlated weakly with the presence of tumor thrombosis, whereas positive TpP (>5.4 microg/ml) correlated strongly with the presence of tumor thrombosis. By multivariant logistic analysis, positive TpP level was found to be a significant predictor of the presence of tumor thrombosis. In contrast, positive D-dimer level was not found to be a significant predictor for predicting tumor thrombosis.. Increased D-dimer and TpP levels in HCC may suggest that fibrinolysis and coagulation occur continuously during tumor progression. This study shows that a positive TpP level is a predictor of tumor thrombosis in HCC, which suggests that TpP may be useful for identifying tumor thrombus in the portal and hepatic veins.

Topics: Biomarkers; Budd-Chiari Syndrome; Carcinoma, Hepatocellular; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Liver Neoplasms; Male; Middle Aged

The aim of the present study was to correlate the preoperative plasma levels of TDP in patients with colorectal cancer to tumor stage, metastasis, and postoperative thromboembolic complications.. Ninety-one patients with colorectal cancer, 20 patients with colorectal adenoma, and 71 patients without neoplastic lesions in the colon or rectum were included in this prospective study. Before surgery, total fibrin and fibrinogen degradation products (TDP) were measured in plasma of all patients with a specific enzyme-linked immunosorbent assay test. Phlebography was performed postoperatively in 82 of 91 patients with colorectal cancer.. Median TDP in plasma of patients with colorectal cancer (805 (range, 339-5,024) ng fibrinogen equivalents (ngFE)) was significantly higher than TDP in patients with colorectal adenoma (591 (range, 417-1386) ngFE/ml) and TDP in patients without neoplastic lesions in the colon (632.8 (range, 180-2622) ngFE/ml; P < or = 0.003). In patients with colorectal cancer and liver metastasis, TDP in plasma (1085.5 (range, 468-5024) ngFE/ml) was significantly higher than in patients with localized tumor growth (753 (range, (339-2,780) ngFE/ml; P < or = 0.02). Twenty of 82 patients (24 percent) with cancer developed thromboembolic complications. TDP was preoperatively significantly higher in this group of patients (1,101 (range, 468-2,167) ngFE/ml) compared with patients without thromboembolic complications (753 (range, 339-5024) ngFE/ml; P < or = 0.04).. Preoperative plasma levels of TDP were elevated in patients with colorectal cancer, especially in patients with liver metastasis and in patients developing postoperative deep venous thrombosis.

Topics: Adenocarcinoma; Adult; Aged; Case-Control Studies; Colorectal Neoplasms; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Postoperative Complications; Prospective Studies; Thromboembolism

Transcatheter arterial chemoembolization with lipiodol and adriamycin was performed in 46 patients with hepatocellular carcinoma (HCC). In 27, this procedure was followed by selective arterial embolization using gelatin sponge particles. Surgical resection was carried out in 5 cases and 13 patients were transplanted (OLT). The aim of the study was to analyze the survival and degree of tumor necrosis. In the nonsurgical group the overall survival was 67% after 24 months in the OKUDA I stage, 31% after 20 months in the OKUDA II stage and 25% after 6 months in the OKUDA III stage. For the patients who underwent surgery, survival was 38% after 20 months in 5 patients who were resected and 72% after 24 months in 13 patients who were transplanted. Transcatheter arterial chemoembolization improves survival in patients who are not operated on, and can be used as a complementary treatment for patients who undergo surgery. A full tumor necrosis was observed in well encapsulated tumors.

Topics: Carcinoma, Hepatocellular; Combined Modality Therapy; Doxorubicin; Embolization, Therapeutic; Fibrin; Hepatectomy; Humans; Iodized Oil; Liver Neoplasms; Liver Transplantation; Neoplasm Staging; Survival Analysis; Time Factors

Patients with liver disease have a variety of coagulation abnormalities. These derangements are of uncertain origin and do not always correlate with disease severity or activity. We have measured the levels and proportions of the total fibrin-related and fibrinogen-related antigens, the principal fibrin (D-dimer) and fibrinogen (D-monomer) degradation fragments and intermediates of fibrin formation (fibrin monomers) in patients with a variety of acute and chronic liver diseases in whom all known other precipitating causes of disseminated intravascular coagulation had been excluded. Fibrin-related and fibrinogen-related antigens were extracted from serum using antihuman fibrinogen-IgG covalently bound to activated amino-phenylthioether paper disks and were subjected to 4% to 11% sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. Fibrin-related and fibrinogen-related antigen proportions were determined by densitometry, and their levels were measured by radioimmunoassay. Levels of total fibrin-related and fibrinogen-related antigens (and D-dimer) were significantly elevated (p less than 0.01) in patients with cirrhosis (121 to 641 ng/ml) and hepatocellular carcinoma (416 to 8,786 ng/ml) when compared with patients with acute viral hepatitis (84 to 322 ng/ml) and control subjects (38 to 186 ng/ml). In addition, D-monomer levels were elevated. These findings strongly suggest that disseminated intravascular coagulation is a component of the coagulopathy of certain liver diseases. Because fibrin-related and fibrinogen-related antigens have anticoagulant, vasoactive and immunosuppressive properties, their elevated presence may be biologically significant in these patients.

Topics: Adult; Antigens; Carcinoma, Hepatocellular; Electrophoresis, Polyacrylamide Gel; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Liver Diseases; Liver Neoplasms; Male; Peptide Fragments

Topics: Female; Fibrin; Granuloma; Humans; Liver; Liver Neoplasms; Lupus Erythematosus, Systemic; Middle Aged

Topics: Aged; Embolization, Therapeutic; Fibrin; Hepatic Artery; Humans; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Ointments

Topics: Batroxobin; Fibrin; Fibrinolysis; Humans; Liver Diseases; Liver Neoplasms; Polymers; Thrombin

Although there have been isolated reports of an acquired abnormal fibrinogen in patients with liver disease, its frequency and clinical significance is not known. In this study 121 consecutive patients with a wide spectrum of hepatic disorders were screened for abnormal fibrin polymerization. A simple colorimetric method using Reptilase was employed. Of 32 patients with proven cirrhosis, 16 (50%) showed abnormal fibrin polymerization. The incidence in decompensated alcoholic cirrhosis was particularly high. The abnormality was also detected in all patients with acute liver failure and seven of 15 with chronic active liver disease. Clinical improvement often correlated with its disappearance. Two patients with primary liver cell tumours demonstrated the abnormal polymerization. In patients with bleeding oesophageal varices the detection of abnormal fibrin polymerization was associated with a poor prognosis. None of the patients with surgical obstructive jaundice (26) or miscellaneous liver disorders (37) had abnormal fibrin polymerization. The occurrence of abnormal fibrin polymerization in liver disease is more frequent than previously suspected and usually signifies severe primary hepatocellular dysfunction. Evidence is presented to support the presence of a primary abnormality of fibrinogen as the cause of impaired fibrin monomer polymerization.

Topics: Batroxobin; Blood Coagulation Tests; Carcinoma, Hepatocellular; Cholestasis; Chronic Disease; Fibrin; Fibrinogen; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Polymers; Thrombin; Time Factors

Ninety-three postoperative patients 1 day to 13 years of age had blood cultures, limulus lysate assay, determination of fibrin degradation products, white blood cell and platelet counts. Seven groups were studied. The limulus lysate assay was often positive (64%) in the presence of gram negative septicemia but there were false positives and negatives. The tests for fibrin degradation products were inconsistent. The white blood cell count was low in babies with gram negative septicemia. One hundred per cent of the infants with gram negative septicemia had a platelet count below 150,000; 71% below 100,000 (average 67,000 septic babies, 257,000 non-septic babies). The drop in platelet count with gram negative septicemia was abrupt---as much as 222,000 in 24 hours. Platelets increased when therapy was effective. Two children with gram negative septicemia had platelet counts of 50,000 and 20,000. The platelet count for patients with gram positive septicemia was 299,000, and above 150,000 in all children with ruptured and non-ruptured appendicitis and major surgery without gram negative septicemia. It was concluded that serial measurements of platelet count in the postoperative infant and child was a rapid and reliable method for early detection of gram negative septicemia and changes in platelet count in response to treatment was an indicator of the effectiveness of therapy.

Topics: Abdominal Muscles; Adolescent; Appendicitis; Bacteria; Bacterial Infections; Blood Cell Count; Blood Platelets; Child; Child, Preschool; Enterocolitis, Pseudomembranous; Escherichia coli Infections; Fibrin; Gangrene; Humans; Infant; Infant, Newborn; Intestinal Obstruction; Klebsiella Infections; Leukocyte Count; Liver Neoplasms; Platelet Aggregation; Postoperative Complications; Pseudomonas Infections; Sepsis; Time Factors

Rabbit antibody to fibrin fragment E (FFE) was used in an immunotherapy model for the treatment of the line-10 ascites variant of a diethylnitrosamine-induced hepatoma in strain 2 guinea pigs. When 0.75 or 1.0 mg of an IgG preparation containing anti-FFE antibody was injected s.c. 6 and 16 days after the injection of a uniformly lethal dose of line-10 tumor cells, complete regression of the i.d. growing tumor was observed in all 18 strain 2 guinea pigs treated. Thus, this therapy appears to be more effective than any BCG or other immunotherapeutic regimen thus far reported for this tumor. No significant anti-tumor effect was noted when normal rabbit IgG or smaller doses (0.25 or 0.50 mg) of the anti-FFE IgG preparation were used. The injection sites exhibited an inflammatory response for 7 to 10 days characterized by erythema and hemorrhage. Since all animals were treated after the metastatic progression of the tumor is known to frequently occur, the long-term tumor-free survival of these animals as well as their resistance to subsequent tumor challenge indicate that the anti-FFE antibody therapy led to systemic tumor immunity.

Topics: Animals; Antibodies; Carcinoma, Hepatocellular; Counterimmunoelectrophoresis; Fibrin; Guinea Pigs; Hypersensitivity, Delayed; Immune Sera; Immunization Schedule; Immunodiffusion; Immunotherapy; Injections, Intradermal; Liver Neoplasms; Neoplasms, Experimental; Rabbits; Skin

The effects of two immunotherapy regimens on the development of an untreated, uniformly lethal transplantable line-10 hepatoma in strain 2 guinea pigs were monitored during treatment of an identical tumor 10 cm away. Line-10 cells were injected intradermally simultaneously at each of two sites. When one site was treated 6 and 16 days later with rabbit antibody against guinea pig fibrin fragment E, the complete regression of the treated tumor, a 25--30% depression in the development of the untreated tumor, and an increased survival time were observed. In another group of animals, when one site was treated 5 days after tumor challenge with syngeneic or xenogeneic "tumor-immune" RNA in a regimen including syngeneic nonsensitive lymphoid cells and tumor-specific antigen, all animals survived after complete and apparently specific regression of the tumors at both the treated and untreated sites. For the RNA regimen, we have shown that immunotherapy of an intradermally established line-10 tumor results in complete abrogation of both the treated and a distant untreated tumor; i.e., demonstrating a systemic effect.

Topics: Animals; Antibodies; Antigens, Neoplasm; Ascitic Fluid; Carcinoma, Hepatocellular; Fibrin; Guinea Pigs; Immunotherapy; Liver Neoplasms; Neoplasms, Experimental; RNA; Time Factors

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Carcinoma, Hepatocellular; Chromatography, Gel; Female; Fibrin; Fibrinogen; Humans; Liver Neoplasms; Middle Aged; Prothrombin Time

Topics: Animals; Cell Transformation, Neoplastic; Collagen; Connective Tissue; Cysts; Dose-Response Relationship, Drug; Fibrin; Hepatic Veins; Injections, Subcutaneous; Kupffer Cells; Liver; Liver Diseases; Liver Neoplasms; Lymphatic System; Lymphoma, Large B-Cell, Diffuse; Male; Microscopy, Electron; Mitosis; Monocytes; Rats; Rats, Inbred Strains; Sarcoma, Experimental; Trypan Blue

Topics: Adult; Biopsy; Extracellular Space; Exudates and Transudates; Female; Fibrin; Graft Rejection; Humans; Inclusion Bodies; Laparotomy; Leukocytes; Liver Neoplasms; Lung; Macrophages; Male; Microscopy, Electron; Middle Aged; Pulmonary Alveoli; Pulmonary Edema; Transplantation, Autologous; Transplantation, Homologous

Topics: Adult; Afibrinogenemia; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Carcinoma, Hepatocellular; Diagnosis, Differential; Female; Fibrin; Fibrinogen; Heparin; Hepatic Encephalopathy; Humans; Liver Neoplasms; Pregnancy; Pregnancy Complications; Prothrombin Time; Spectrophotometry; Thrombin

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