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)

Epithelial ovarian cancer (EOC) represents the most frequent cause of death in the United States from a cancer involving the female genital tract. Contributing to the overall poor outcome in EOC patients, are the metastases to the peritoneum and stroma that are common in this cancer. In one study, cDNA microarray analysis was performed on fresh tissue to profile gene expression in patients with EOC. This study showed a number of genes with significantly altered expression in the pelvic peritoneum and stroma, and in the vicinity of EOC implants. These genes included those encoding coagulation factors and regulatory proteins in the coagulation cascade and genes encoding proteins associated with inflammatory responses. In addition to promoting the formation of blood clots, coagulation factors exhibit many other biologic functions as well as tumorigenic functions, the later including tumor cell proliferation, angiogenesis, invasion, and metastasis. Coagulation pathway proteins involved in tumorigenesis consist of factor II (thrombin), thrombin receptor (protease-activated receptors), factor III (tissue factor), factor VII, factor X and factor I (fibrinogen), and fibrin and factor XIII. In a recent study we conducted, we found that factor XII, factor XI, and several coagulation regulatory proteins, including heparin cofactor-II and epithelial protein C receptor (EPCR), were also upregulated in the peritoneum of EOC. In this review, we summarize evidence in support of a role for these factors in promoting tumor cell progression and the formation of ascites. We also discuss the different roles of coagulation factor pathways in the tumor and peritumoral microenvironments as they relate to angiogenesis, proliferation, invasion, and metastasis. Since inflammatory responses are another characteristic of the peritoneum in EOC, we also discuss the linkage between the coagulation cascade and the cytokines/chemokines involved in inflammation. Interleukin-8, which is considered an important chemokine associated with tumor progression, appears to be a linkage point for coagulation and inflammation in malignancy. Lastly, we review findings regarding the inflammatory process yielded by certain clinical trials of agents that target members of the coagulation cascade in the treatment of cancer. Current data suggest that disrupting certain elements of the coagulation and inflammation processes in the tumor microenvironment could be a new biologic approach to cancer therapeutics.
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PMID:Ovarian cancer, the coagulation pathway, and inflammation. 1596 48

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

Hemostatic disorders can be found in approximately 90% of cancer patients, but clinical expression in only 15%. Hemorrhagic complications are more frequent in acute leukaemia; solid tumors are often associated with deep venous thromboses (DVP). Disseminated intravascular coagulation syndrome (DICS) can be latent or acute, and has various clinical presentations, occurring in the course of many serious conditions including cancer. Patients have higher morbidity and mortality. Irrespective of the etiology, DICS can be revealed by a wide variety of clinical manifestations, from mild biological hemostasis disorders, to intravascular or extravascular microthromboses or lethal hemorrhagic events. We report the case of a 45-year-old female with non-small-cell lung cancer with metastases at diagnosis. The patient developed and finally died of numberous thromboembolic events subsequent to DICS. This case illustrates some rather rare complications of DICS and offers the opportunity to discuss the main therapeutic goal in this situation, i.e. to modulate the disproportionate production of thrombin, inducing thromboses and/or hemorrhages by consumption of the cellular and plasmatic coagulation factors. This means a symptomatic and mostly etiologic treatment, especially chemotherapy which can in itself provoke thromboembolic events.
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PMID:[Disseminated intravascular coagulation syndrome and thromboembolic complications of non-small-cell lung cancer. A case report]. 1745 85

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

In the mid 1800s Trousseau observed cancer-associated thrombosis, of which the underlying pathogenesis still remains unknown. We performed a prospective study on platelet-derived microparticles (PMP) and their procoagulant potential in breast cancer patients. Fifty-eight breast cancer patients and 13 women with benign breast tumors were included in the study. Microparticles (MP) were examined by electron microscopy and FACS analysis using labels for annexin V (total numbers), CD61 (PMP), CD62P and CD63 (activated platelets), CD62E (endothelial cells), CD45 (leukocytes) as well as CD142 (tissue factor). Prothrombin fragment 1+2 (F1+2) and thrombin generation were measured as blood coagulation markers. Numbers of annexin V+-MP were highest in breast cancer patients with larger tumor size (T2; median = 5,637 x 10(6)/l; range = 2,852-8,613) and patients with distant metastases (M1; median = 6,102 x 10(6)/l; range = 3,350-7,445), and differed significantly from patients with in-situ tumor (Tis; median = 3,220 x 10(6)/l; range = 2,277-4,124; p = 0.019), small tumor size (T1; median = 3,281 x 10(6)/l; range = 2,356-4,861; p = 0.043) and women with benign breast tumor (median = 4,108 x 10(6)/l; range = 2,530-4,874; p = 0.040). A total of 82.3% of MP were from platelets, 14.6 % from endothelial cells and 0.3% from leukocytes. Less than 10% of PMP showed degranulation markers. Larger tumor size (T2) and metastases correlated with high counts of PMP and with highest F1+2 levels. Since prothrombin levels and thrombin generation did not parallel MP levels, we speculate that MP act in the microenvironment of tumor tissue and may thus not be an exclusive parameter reflecting in-vivo procoagulant activity.
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PMID:Platelet-derived microparticles and coagulation activation in breast cancer patients. 1884 Dec 90

Cancer progression is facilitated by blood coagulation. Anticoagulants, such as Hirudin and low molecular weight heparins (LMWHs), reduce metastasis mainly by inhibition of thrombin formation and L- and P-selectin-mediated cell-cell adhesion. It is unknown whether the effects are dependent on cancer cell type. The effects of anticoagulants on tumor development of K1735 and B16 melanoma cells and CT26 colon cancer cells were investigated in mouse lung. Tumor load was determined noninvasively each week up to day 21 in all experiments using bioluminescence imaging. Effects of anticoagulants on tumor development of the three cell lines were correlated with the fibrin/fibrinogen content in the tumors, expression of tissue factor (TF), protease activated receptor (PAR)-1 and -4 and CD24, a ligand of L- and P-selectins. Hirudin inhibited tumor development of B16 cells in lungs completely but did not affect tumor growth of K1735 and CT26 cells. Low molecular weight heparin did not have an effect on K1735 melanoma tumor growth either. TF and PAR-4 expression was similar in the three cell lines. PAR-1 and CD24 were hardly expressed by K1735, whereas CT26 cells expressed low levels and B16 high levels of PAR-1 and CD24. Fibrin content of the tumors was not affected by LMWH. It is concluded that effects of anticoagulants are dependent on cancer cell type and are correlated with their CD24 and PAR-1 expression.
Clin Exp Metastasis 2009
PMID:Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung. 1906 86

An 80 years old male patient was admitted in our hospital with massive haematomas in the left forearm, chest and abdominal wall accompanied by intense back pain symptoms. Laboratory evaluation showed anemia, mild thrombocytopenia and elevated lactate dehydrogenase and alkaline phosphatase levels and normal concentrations of all the other biochemical parameters. Study of the coagulation status demonstrated prolonged thrombin time (TT), low fibrinogen levels--0.98 g/l while plasminogen, antithrombin III (AT III) and protein C levels were found to be within normal range. Computed tomography scans of the head, chest and abdomen showed an enlarged infiltrative prostate, osteolytic bone lesions in vertebras L5-S1 and a large haematoma of the abdominal wall as the only pathologic findings. Very high levels of the prostate specific antigen indicated the possible existence of a prostate carcinoma with metastases to the vertebral column that resulted in elevated alkaline phosphate and lactate dehydrogenase levels. There were no signs of liver involvement and impaired hepatic synthetic function. Based on the results of the laboratory tests we concluded that the cause of the bleeding disorder in our patient was an acquired hypofibrinogenemia, which is a very rare paraneoplastic phenomenon. The patient was treated with daily transfusions of cryoprecipitate with no long-term improvement. Then the specific anti-tumor therapy (ciproteron acetate) was initiated, and two weeks later, fibrinogen concentration and TT returned to normal values.
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PMID:Paraneoplastic bleeding disorder due to isolated hypofibrinogenemia: a case report. 1924 Aug 23

Diverse oncogenic transformations result in the constitutive expression of tissue factor (TF) in cancer cells. The local and systemic activation of the coagulation cascade has long been a recognized hallmark for aggressive cancer, but genetic mouse models and new experimental therapeutics have only recently demonstrated crucial roles for TF initiated cell signaling in the pathogenesis of cancer. On tumor cells, the TF-VIIa binary complex mediates activation of protease activated receptor (PAR) 2 and thereby shapes the tumor microenvironment by inducing an array of proangiogenic and immune modulating cytokines, chemokines, and growth factors. PAR2 also uniquely triggers tumor cell migration by G protein-independent pathways through beta-arrestin scaffolding. Metastatic tumor cells use additional signaling networks of the coagulation cascade by activating PAR1 through thrombin or the ternary TF-VIIa-Xa signaling complex in the vascular and potentially lymphatic system. Selective antagonists of TF-VIIa-PAR2 signaling may be used as antiangiogenic therapy without increasing the risk of bleeding, whereas coagulation and associated signaling pathways on platelets and other host cells may be targeted for therapeutic benefit in advanced cancer and metastatic disease.
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PMID:Tissue factor and PAR2 signaling in the tumor microenvironment. 1966 89

The expression of tissue factor (TF) in tumors reportedly exacerbates the aggressiveness of several types of cancers. The shedding of TF-containing membrane particles is believed to influence the ability of tumors to expand and metastasize, and these microparticles may also be harmful in the onset of disseminated intravascular coagulation in specific cancers. Furthermore, the intracellular signaling that is elicited after the formation of the TF / coagulation factor VIIa complex at the cell membrane modulates the activity of adhesion molecules and mitogen-activated protein (MAP) kinases. To evaluate whether TF overexpression in tumor cells modulates its shedding and neighboring stromal cells by its catalytic or intracellular activity, TF-GFP (green fluorescent protein) and a tailless form (TFDeltaC-GFP) were stably expressed in the rat Morris hepatoma and human HT1080 fibrosarcoma cell lines. Both TF proteins were efficiently produced by tumor cells and functionally active, and their clotting activity could be blocked by the active site-inhibited factor VIIa (ASIS). TF-expressing tumorigenic cells produced a soluble factor that increased the migration of arterial smooth muscle cells in vitro. This effect was abrogated by ASIS and the PAR-1 receptor antagonist ATAP-2, showing that it is dependent on the proteolytic activity of the TF ligand factor VIIa and the thrombin-activated cell membrane receptor. We propose that TF-containing microparticles that are released in the culture medium by tumor cells influence the migratory behavior of neighboring stromal cells, thus aiding the cancer cell's tumorigenic potential.
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PMID:Tumor cells expressing tissue factor influence the migration of smooth muscle cells in a catalytic activity-dependent way. 1979 20

Platelets (PLT) are the smallest yet highly reactive components of the circulatory system. Microvesicles (platelet-derived microvesicles - PMV), also known as microparticles or microplatelets (platelet-derived microparticles - PMP), are released from platelets upon stimulation by thrombin, collagen or others platelet agonists. Both PLT and PMP play a role in haemostasis and mediate signal transmission between cells, especially cancer cells, thus modulating their functions. Moreover, these two platelet populations participate in transcellular exchange of information, affect immune responses and angiogenesis, which may facilitate tumour growth and development of distant metastases. Their role in tumour progression has been recognized, but the mechanism of their action remains still unclear. Assessment of PMP as a diagnostic and prognostic marker in various disorders is currently a subject of intense investigation.
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PMID:[A new look at platelets and microparticles, including their role in haemostatic disorders and progression of neoplastic disease]. 2012 Jul 15


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