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

Characteristics of multicentric hepatocellular carcinomas (HCCs) remain obscure. We therefore aimed to clarify them and compare them with HCC with intrahepatic metastases. A series of 118 patients who had definite hepatitis C viral status and multinodular HCC were divided into two groups: a multicentric occurrence (MO) group (n = 38), with multicentric HCCs; and an intrahepatic metastasis (IM) group (n = 80), with HCC having intrahepatic metastases. Clinicopathologic variables, including the patient's survival and disease-free survival rates, were compared between the MO and IM groups. Univariate analysis revealed the presence of esophageal varices, the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, hepaplastin test, gamma-globulin, the histologically active hepatitis, tumor size, des-gamma-carboxy prothrombin > 0.1 AU/ml, positive portal vein invasion, and histologic grade as discriminating factors. The MO score to differentiate multicentric HCCs from intrahepatic metastatic HCCs was determined using the following four independent factors selected by a stepwise regression analysis: the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, tumor size, and histologic grade. The sensitivity and specificity of the MO scores using those factors were 84% and 70%, respectively, when the cutoff value was 0.4. The disease-free survival rate in the MO group was similar to that in the IM group, whereas the survival rate in the MO group was significantly better than that in the IM group. The multivariate analysis revealed the multicentric occurrence of HCC as one of the independent prognostic factors. Clinicopathologic factors differentiating multicentric HCCs from intrahepatic metastatic HCCs were the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, small tumor size, and low histologic grade.
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PMID:Characteristics of multicentric hepatocellular carcinomas: comparison with intrahepatic metastasis. 1157 81

Prothrombin, a protein involved in blood coagulation, is a plasma glycoprotein composed of the Gla domain, two adjacent kringle domains, and a serine protease domain. Kringles are triple-disulfide-loop folding domains, which are found in several other blood proteins. In this study, we showed that recombinant human prothrombin kringle-1, -2. and -1-2 (rk-1, -2, -1-2) all have potent anti-angiogenic activities, which inhibit Lewis lung carcinoma (LLC) tumor growth and metastases. Recombinant human prothrombin kringles were expressed by an E. coli expression system and purified to apparent homogeneity from crude E. coli extracts. Purified rk-1, -2, -1-2 migrated with a molecular mass of 14, 19, and 31 kDa, respectively, on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. rk-1, -2, -1-2 exhibited potent inhibitory effects on bFGF-stimulated bovine capillary endothelial cell growth with half-maximal concentrations (ED50) of approximately 41, 55, and 156 nM, respectively. All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane (CAM) of chick embryos at a dose of 20 microg. Systemic administration of rk-1, -2, -1-2 at a dose of 0.5 mg/kg/day suppressed the growth of primary LLC and at dose of 0.5 and 1.0 mg/kg/day inhibited LLC metastases in C57BL6/J mice lungs through their anti-angiogenic effects.
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PMID:Recombinant human prothrombin kringles have potent anti-angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases. 1283 Oct 60

A number of studies indicate that coagulation proteases play significant roles in cancer biology. Melanoma is a highly metastatic cancer, and there is evidence that thrombin contributes to this aggressive pattern. However, few studies correlate this type of cancer with formation of the prothrombinase complex, which is responsible for conversion of prothrombin into thrombin in the coagulation system. The aim of this study was to investigate the assembly and regulation of prothrombinase complex on the murine melanoma cell line, B16F10. B16F10 cells were unable to activate prothrombin except when previously incubated with factor Xa. This effect was dependent on factor Xa binding to cell membranes, since no activation was detected with Gla-domainless factor Xa. The thrombin formation by B16F10-bound factor Xa was enhanced approximately 10 fold in the presence of factor Va, indicating the assembly of prothrombinase complex. Differently from platelets, B16F10-assembled prothrombinase complex was inhibited by prothrombin fragment 1 but not by fragment 2. In addition, bothrojaracin, a specific ligand of proexosite I on prothrombin, caused a significant decrease in the zymogen activation. Our data demonstrate that B16F10 melanoma cells generate thrombin by promoting assembly of the prothrombinase complex. This ability might be correlated with the increased metastatic potential of this cell line. Moreover, B16F10-assembled prothrombinase complex seems to be modulated in a different way from that found for the physiological complex assembled on platelets.
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PMID:Assembly and regulation of prothrombinase complex on B16F10 melanoma cells. 1556 63

Chondrosarcoma is a malignant disease of cartilage. Systemic embolisation usually arises from cancerous invasion of pulmonary vessels or the left atrium but cerebral embolisation or ischaemia is rarely recognised. We report a man with left leg amputation for tibial myxoid chondrosarcoma who suffered multiple cerebral embolisms one year later. Cerebral angiography and aortogram did not reveal luminal stenosis and a cardiac survey was normal. Lupus anticoagulant (LAC) and a prolonged activated partial thromboplastin time were detected. A molecular mimicry between prothrombin and paracrine hormones may have accounted for his LAC. A procoagulant autoantibody reacting against metastatic cancer cells may contribute to cancerous thrombosis, such as in chondrosarcoma.
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PMID:Chondrosarcoma, lupus anticoagulant and cerebral ischaemia. 1585 Oct 89

Cancer procoagulant (CP) is a cysteine proteinase that may be produced by malignant and foetal tissue. The possible role of CP in the pathogenesis of cancer-related thrombosis has been suggested recently. The purpose of the study was to evaluate coagulation prothrombotic markers and their relation to CP concentration in the blood of patients with gastrointestinal adenocarcinomas (GIAC). The study group consisted of 45 patients with confirmed diagnosis of adenocarcinoma (stomach, 18 patients; colon, 27 patients) and without evident metastatic disease. In 24 patients further observation showed metastases. The control group for CP was composed of 10 healthy subjects. Blood samples were drawn on the admission day, before any treatment. Among 45 patients with GIAC, deep venous thrombosis was observed in two (4.4%). In all patients the CP activity in the serum was found, and the mean CP activity shortened the coagulation time almost three times compared with the healthy control group. Also, the mean thrombin-antithrombin complex concentration was above the normal range. A significant elevation of the mean prothrombin fragment 1+2 plasma content in this group of patients was noticed. Despite these observations, CP remained within the normal range and did not correlate with thrombin-antithrombin complex or prothrombin fragment 1+2 plasma concentrations. A positive correlation was observed between serum CP and fibrinogen concentration, and a negative correlation between CP and free protein S plasma content (P = 0.04 and P = 0.025, respectively). A negative correlation between activated protein C resistance ratio and protein C activity in the plasma was confirmed. Protein C activity in the plasma showed a correlation with free protein S plasma content. Analysis of factors influencing the activated partial thromboplastin time revealed the presence of antiphospholipid antibodies in seven persons from the study group (in three cases of IgG and in four cases of IgM class). Our data suggest that CP is a minor risk factor for deep venous thrombosis in GIAC patients. To confirm this, however, the number of patients and controls should be larger. After 3 years of observation, the follow-up in 10 living GIAC patients showed nobody with thromboembolic disease.
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PMID:Cancer procoagulant in patients with adenocarcinomas. 1626 26

Ascites in patients with breast cancer is uncommon. We report the case of a 70-year-old woman with breast cancer and ascites caused by portal hypertension due to metastatic liver infiltration. There was no evidence of peritoneal carcinomatosis and the prothrombin index was normal. Portal hypertension was confirmed by increased hepatic venous pressure gradient. Histological examination of a liver biopsy obtained by the transjugular route demonstrated infiltration by malignant cells from the breast tumor. This case shows that, infiltration of the liver by metastases from breast cancer may lead to ascites due to portal hypertension, even in the absence of hepatic failure.
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PMID:[Ascites due to portal hypertension from breast cancer- related metastatic liver infiltration]. 1688 77

Angiogenesis, a multi-step process which involves endothelial cell proliferation, adhesion, migration, and basement membrane (BM) degradation, is essential for tumor metastasis. Here we show that recombinant human prothrombin kringle-2 (rk-2) inhibited bovine capillary endothelial cell migration with an IC(50) (concentration for half maximal inhibition) of 38 nM and inhibited adhesion to extracellular matrix (ECM) proteins. Because tumor metastasis requires angiogenesis, we examined whether rk-2 could inhibit metastases induced by injection of B16F10 melanoma cells into mice. The results revealed that the metastatic tumors in mouse lung were markedly decreased in a dose-dependent manner and acute lung injury induced by B16F10 melanoma metastasis was diminished by systemic rk-2 treatment. In immunohistochemical analysis, rk-2 reduced expression of vascular endothelial growth factor, which is a potent angiogenic activator and neovascularization in the mouse lung. Also, rk-2 diminished the expression of matrix metalloproteinase-2 and -9 in the mouse lung which induces tumor metastasis and angiogenesis. These data suggest that inhibition of B16F10 melanoma metastasis by rk-2 was caused by inhibition of neovascularization and reduction of matrix metalloproteinase expression.
Clin Exp Metastasis 2006
PMID:Recombinant human prothrombin kringle-2 inhibits B16F10 melanoma metastasis through inhibition of neovascularization and reduction of matrix metalloproteinase expression. 1718 28

Postoperative liver failure (PLF) is a rare but often fatal complication of major hepatic resection. Use of orthotopic liver transplantation (OLT) for PLF remains undefined. We conducted a retrospective review of 435 patients who underwent hepatic resection between 1990 and 2004; 9 of them (2.0%) developed PLF. Indications for resection included primary hepatic malignancies (8), colonic metastases (2), and echinococcic cyst (1); all resections were multisegmental, 6 were extended, and 2 were lobectomies. A total of 7 patients underwent OLT at a mean of 25 days after resection. Patients developing PLF had significantly lower preoperative platelet counts and significant elevations of total bilirubin, direct bilirubin, prothrombin time, and international normalized ratio (INR) by postoperative day 2. Pathological cirrhosis and extended right lobectomy were associated with significantly increased risk of PLF. Following OLT, there were no in-hospital deaths, but 1 patient required retransplantation for primary nonfunction. Mean survival with and without OLT was 42.2 and 1.4 months, respectively (P = 0.03). Following OLT, 1- and 5-yr patient survivals were 88% and 40%, respectively; 1- and 5-yr graft survivals were 75% and 34%, respectively. In conclusion, patients with low platelets, biopsy-proven cirrhosis, or those undergoing extended resection are at increased risk for PLF. OLT for PLF has significant morbidity but allows salvage of an otherwise fatal condition.
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PMID:Postresection hepatic failure: successful treatment with liver transplantation. 1745 56

The microvascular invasion of cancer cells (mvi) is a good prognostic factor after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The aim of this study is to predict mvi in patients with HCC who were candidates for OLT. We studied 218 patients with HCC resections who had HCC without any extrahepatic metastases and vascular invasion detected during preoperative evaluation. We analyzed the clinico-pathological data of these patients to predict the mvi presence. The mvi prediction scoring system was made and the accuracy of this system was examined using independent clinico-pathologic factors. The size and histological grade of the tumor were significantly correlated with the mvi. The des-gamma-carboxy prothrombin (DCP) is a mvi predictor. The sensitivity of our mvi prediction system was 75% and the specificity was 85% in 32 patients who underwent living-donor liver transplantations for HCC. Our study shows that besides the tumor size and histological grade, a measurement of the serum DCP levels could be a good predictor for mvi. A tumor biopsy and a preoperative measurement of DCP could improve the selection of patients with HCC for OLT. Our scoring system for mvi provides us a precise prediction of the presence of mvi.
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PMID:The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference to the serum levels of des-gamma-carboxy prothrombin. 1732 37

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.
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PMID:Activated coagulation factors in human malignant effusions and their contribution to cancer cell metastasis and therapy. 1754 6


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