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

Tissue factor is a cell surface glycoprotein responsible for initiating the extrinsic pathway of coagulation. Many tumor cell homogenates and intact tumor cells have been shown to contain tissue factor activity. Immunohistochemical studies show that many tumors associated with Trousseau's syndrome express tissue factor on their cell surfaces. Tumor cells shed membrane fragments which carry tissue factor that can account for the activation of the clotting system. Tumor cells also produce soluble substances that can induce tissue factor expression on host cells, such as endothelium and monocytes, at sites distant from the tumor. Although, all the functional TF molecules are localized on the outer cell membrane in many tumor cells, the procoagulant activity on the intact cell surface is largely dormant and can be greatly enhanced upon cell injury or damage. Tissue factor procoagulant activity on the cell surface can be modulated by alterations in the plasma membrane without loss of cell viability. Tissue factor activity on cell surfaces is largely regulated by a plasma inhibitor, tissue factor pathway inhibitor. This inhibitor binds to both functional and non-functional tissue factor/VIIa complexes on the cell surface and prevents non-functional tissue factor/VIIa complexes from becoming functional after cell injury or lysis. Heparin, but not warfarin, therapy is effective in preventing the occurrence of devastating thrombotic events in patients with Trousseau's syndrome and the reason(s) for this are still unknown.
Cancer Metastasis Rev 1992 Nov
PMID:Tissue factor as a tumor procoagulant. 142 17

Metastasis is a multistep process which requires highly adapted interactions of tumor cells with host target organs. Compared with nonmetastatic cells, metastatic human melanoma cells express 1000-fold higher level of tissue factor (TF), the major cellular initiator of the plasma coagulation protease cascades. To explore whether TF may contribute to metastatic tumor dissemination, we analyzed the effect of specific inhibition of TF function on human melanoma metastasis in severe combined immunodeficient (SCID) mice. Using species-specific antibodies to TF, we demonstrate that initial adherence in insufficient for successful tumor cell implantation in a target organ. Rapid arrest of human tumor cells in the lungs of mice was not diminished by inhibition of TF. However, inhibition of TF receptor function and consequent reduction in local protease generation abolished prolonged adherence of tumor cells, resulting in significantly reduced numbers of tumor cells retained in the vasculature of the lungs. The growth of pulmonary metastases was also significantly inhibited by a blocking anti-TF monoclonal antibody and Fab fragments thereof, whereas a noninhibitory antibody lacked antimetastatic effects. Cell surface expression of functional TF thus contributes to melanoma progression by allowing metastatic cells to provide requisite signals for prolonged adhesive interactions and/or transmigration of tumor cells across the endothelium, resulting in successful metastatic tumor implantation.
 ...
PMID:Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. 146 6

Somatostatin is a regulatory hormone or tissue factor which plays an inhibitory role in the normal regulation of several organ systems, including the central nervous system, hypothalamus and pituitary gland, the gastrointestinal tract and the exocrine and endocrine pancreas. Sandostatin is an analogue of somatostatin which has characteristics which makes it a better compound for clinical use than native somatostatin: it inhibits GH preferentially over insulin. It has a long half-life in the circulation, causing a prolonged inhibitory effect in somatostatin-responsive target organs. It is active after subcutaneous administration and rebound hypersecretion does not occur. Sandostatin is very well tolerated by most patients. Somatostatin receptors remain present on a variety of tumours which arise in tissues that contain these receptors normally. High numbers of somatostatin receptors have been found on GH-secreting pituitary tumours and on most metastatic endocrine pancreatic tumours and carcinoids. Sandostatin treatment ameliorates clinical symptoms in most acromegalic patients while GH hypersecretion and elevated concentrations of circulating IGF-I are well controlled. In most patients hormonal hypersecretion from endocrine pancreatic tumours and carcinoids is also suppressed during Sandostatin therapy. This results in an instant improvement in the quality of life. There is preliminary evidence of control of tumour growth. The presence of high numbers of somatostatin receptors on tumours enables in vivo receptor-imaging, with 123iodine coupled to a somatostatin analogue. This newly developed technique provides for the first time the possibility of localization of the primary tumours and their metastases and a prediction of which patients may respond to treatment with Sandostatin. Theoretically this somatostatin-receptor imaging technique represents a new approach which may be extended to other receptor-containing tumours. Therefore it may provide a new, powerful alternative to tumour localization performed with monoclonal antibody technology. Another potential development is the use of beta-emitting isotopes coupled to somatostatin analogues for therapeutic irradiation. Somatostatin analogues exert potent inhibitory effects on the growth of a variety of experimental tumour models in animals. Several mechanisms of action have been proposed including the direct antiproliferative effects of somatostatin and its analogues in a variety of tumour cell cultures. Most well-differentiated human brain tumours like meningiomas and low-grade astrocytomas contain somatostatin receptors, while undifferentiated brain tumours mainly contain EGF receptors. Fifteen percent of human breast carcinomas contain somatostatin receptors; those which do have a better prognosis. It can be concluded that somatostatin is an endogenous, naturally occurring inhibitory growth factor.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:The clinical use of somatostatin analogues in the treatment of cancer. 197 66

The paraneoplastic syndrome (PNS) is an association of symptoms and signs not directly related to the site or local manifestations of a malignant tumor or its metastases. Hematologic abnormalities as PNS include erythrocytosis, anemia, neutrophilia, neutropenia, eosinophilia, thrombocytosis, thrombocytopenia, venous thromboembolism and disseminated intravascular coagulation (DIC). These abnormalities are, by and large, due to the production of biologically active growth factors, hormones or as yet unidentified "humors" by the tumor. As our understanding of growth factors controlling hematopoiesis has increased in recent years, the biologic basis of hematologic PNS are better understood. For instance, tumor-associated neutrophilia is now known to be caused by the production of G-CSF by the tumor. The mechanism by which tumor causes thromboembolism have also been extensively investigated. Cancer cells induce platelet aggregation both in vitro and in vivo. Platelet aggregating material has been isolated and partially characterized from tumor cells. The involvement of platelet glycoprotein II b/IIIa in the tumor-platelet interaction has also been shown. Malignant cells contain a unique procoagulant, cancer procoagulant A, that directly activates factor X. Together with tissue factor, this procoagulant appears to have been contribute to a high incidence of thromboembolism in cancer patients. Better understanding of hematologic PNS is important for clinical care of the patients with cancer.
 ...
PMID:[Paraneoplastic syndrome hematologic abnormalities]. 200 36

We studied the effects on platelet function of cells isolated from freshly dissociated human tumor tissues (11 breast carcinomas, 9 colon carcinomas and 1 lymph node metastasis from melanoma) obtained at surgery as compared with cultured human tumor cells: namely, human melanoma 1402 cell line derived from a primary tumor and two lines derived from lymph node metastases (ME 7110/2 and Me 665/1) as well as a human hepatoma cell line (Hep G2). The three melanoma cell lines activated platelets by producing ADP, as evidenced by the inhibitory effect of apyrase and by the direct measurement of the agonist in the supernatants of tumor cell suspensions; this production was much greater by the cells derived from metastases than by the cells derived from the primary tumor. On the other hand, aggregation induced by Hep G2 hepatoma cells was unaffected by apyrase and was inhibited by hirudin or concanavalin A, suggesting that the cells aggregate platelets by producing thrombin, probably through tissue factor activity of the cells themselves. Cells isolated from 16 of the 21 human tumor tissues possessed a potent platelet-aggregating effect, which was not inhibited by apyrase, hirudin or concanavalin A, but was virtually abolished by the cysteine protease inhibitors iodoacetic acid or p-hydroxymercuri-phenylsulfonate. Collectively, our data demonstrate that cells isolated from freshly dissociated tumor tissues activate platelets through tumor-associated cysteine proteinases rather than by the ADP- or thrombin-dependent mechanisms characteristic of cultured human tumor cell lines.
Invasion Metastasis 1989
PMID:Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. 276 27

Cultured SK-OS-10 cells (human osteogenic sarcoma metastatic to lung) shed microvesicles (dia. 300-1000 nm) that contained procoagulant and proaggregatory activities inhibitable by hirudin, by anti-tissue factor antibody and by phospholipase A2. These results show that SK-OS-10 cells belong to a group including U87MG human glioblastoma and HL-60 promyelocytic leukemia in which these activities are due to a thrombin-dependent mechanism arising from the presence of tissue factor on the surface of the tumor cells and their shed microvesicles.
Invasion Metastasis 1987
PMID:Tissue factor-dependent activation of platelets by cells and microvesicles of SK-OS-10 human osteogenic sarcoma cell line. 303 40

Several studies have established a link between blood coagulation and cancer, and more specifically between tissue factor (TF), a transmembrane protein involved in initiating blood coagulation, and tumor metastasis. In the study reported here, a murine model of human melanoma metastasis was used for two experiments. (i) The first experiment was designed to test the effect of varying the level of TF expression in human melanoma cells on their metastatic potential. Two matched sets of cloned human melanoma lines, one expressing a high level and the other a low level of the normal human TF molecule, were generated by retroviral-mediated transfections of a nonmetastatic parental line. The metastatic potential of the two sets of transfected lines was compared by injecting the tumor cells into the tail vein of severe combined immunodeficiency (SCID) mice and later examining the lungs and other tissues for tumor development. Metastatic tumors were detected in 86% of the mice injected with the high-TF lines and in 5% of the mice injected with the low-TF lines, indicating that a high TF level promotes metastasis of human melanoma in the SCID mouse model. This TF effect on metastasis occurs with i.v.-injected melanoma cells but does not occur with primary tumors formed from s.c.-injected melanoma cells, suggesting that TF acts at a late stage of metastasis, after tumor cells have escaped from the primary site and entered the blood. (ii) The second experiment was designed to analyze the mechanism by which TF promotes melanoma metastasis. The procedure involved testing the effect on metastasis of mutations in either the extracellular or cytoplasmic domains of the transmembrane TF molecule. The extracellular mutations introduced two amino acid substitutions that inhibited initiation by TF of the blood-coagulation cascade; the cytoplasmic mutation deleted most of the cytoplasmic domain without impairing the coagulation function of TF. Several human melanoma lines expressing high levels of either of the two mutant TF molecules were generated by retroviral-mediated transfection of the corresponding TF cDNA into the nonmetastatic parental melanoma line, and the metastatic potential of each transfected line was tested in the SCID mouse model. Metastases occurred in most mice injected with the melanoma lines expressing the extracellular TF mutant but were not detected in most mice injected with the melanoma lines expressing the cytoplasmic TF mutant. Results with the extracellular TF mutant indicate that the metastatic effect of TF in the SCID mouse model does not involve products of the coagulation cascade. Results with the cytoplasmic TF mutant indicate that the cytoplasmic domain of TF is important for the metastatic effect, suggesting that the TF could transduce a melanoma cell signal that promotes metastasis.
 ...
PMID:Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. 766 69

A body of evidence that vascular-mediated damage occurs in murine tumours after many existing forms of anti-tumour therapy is rapidly accumulating (see Gray Conference Proceedings edited by Moore & West, 1991). Rapid conventional screens of cells in vitro or using leukaemias of lymphomas will not detect this mode of action and such screens will therefore miss effective agents. A change in the approach to experimental cancer therapy is needed to ensure that this important new avenue is fully investigated. Solid tumours will need to be studied and the importance of specific tumour cell biochemistry (e.g. on tissue factor procoagulant activity), of endothelial status and the immunocompetence of the host are all likely to be important. It is a subject of considerable debate at present whether transplanted subcutaneous mouse tumours are adequate models and whether they will reflect the response of spontaneous tumours, or even of transplants into other sites. Xenografts are not likely to be appropriate if the immuno-suppressed hosts lack the cells needed for the cytokine component of the pathway. The strategy of design and screening of new agents, for scheduling of existing agents and particularly the sequencing of adjunctive therapies are likely to be completely different for the "direct" tumor cell or "indirect" vascular-mediated approaches. It may eventually be appropriate to combine vascular manipulation with direct cytotoxicity aimed at malignant cells but the two mechanisms must be recognized as distinct entities and considered separately before attempting to coordinate them. It is important therefore to identify the "hallmarks" of vascular mediated injury and the means by which this can be distinguished from direct cell kill. These may be detectable in the tumour response but clues can also be gained from the side effects that are seen in normal tissues both with existing and with novel therapies (Figure 7). The appeal of vascular-mediated ischaemic therapy is that it is systemic and will have the potential of being effective on any tumour with a newly evoked vascular network, i.e. of about 1 mm in diameter, but it will be even more effective on large tumours than on small. Thus it should affect both large primary tumours and disseminated small metastases. The studies with many different anti-cancer agents have illustrated the potential complexity of responses that can appear to cause tumour cell death by collapse or occlusion of the blood supply. They have also focused attention on features of disparate agents, e.g. TNF, FAA, PDT, which may share similar pathways. No single feature of neovasculature can be highlighted as the sole route by which such antivascular therapy should be targeted. Rapid proliferation of the endothelial cells may prove to be a target, but it also influences differentiation characteristics, so that the immature cells will function abnormally. The permeability of these poorly formed vessels may lead to extravasation of proteins leading to increase interstitial pressures and by this means to an imbalance between intravascular and extravascular pressures and hence to collapse of the thin-walled vessels. Changes in systemic blood pressure, cardiac output, viscosity or coagulation and especially a redistribution of regional perfusion would all have differential effects in tumours and normal vessels. Clearly both vascular patho-physiology and the complexity of endothelial cell function and its imbalance in neovasculature will be important in understanding the mechanism of action of antivascular strategies. This very challenging boundary between oncology and a number of other medical and biological fields promises to lead to altered attitudes to existing therapies and the discovery of completely new classes of anti-cancer agents. The next decade should translate into clinical benefit for patients if the progress in this field continues to be as rapid as it has been in the late eighties. We must now determine what characteristics make one tumour more sensitive than another to agents such as heat, PDT, cytokines and FAA, and learn how to extrapolate from those rodent tumours to the human.
 ...
PMID:Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. 768 69

In this study, we examined the effect of triflavin, an Arg-Gly-Asp (RGD)-containing snake venom peptide, on human cervical carcinoma (HeLa) cell- and B16-F10 mouse melanoma cell-induced platelet aggregation (TCIPA) in heparinized platelet-rich plasma. TCIPA appears to play an important role in the development of certain experimental tumor metastases. Two ADP-scavenging agents, apyrase (10 U/ml) and creatine phosphate (CP) (5 mM)/creatine phosphokinase (CPK) (5 U/ml) completely inhibited B16-F10 TCIPA, but hirudin (5 U/ml) had no effect. In contrast, apyrase and CP/CPK did not inhibit HeLa TCIPA while hirudin completely inhibited it. Furthermore, HeLa cells initially induced platelet aggregation and then blood coagulation at a later stage. In addition, HeLa cells shortened, in a concentration-dependent manner, the recalcification time of normal as well as factor VIII- and IX-deficient human plasma, but did not affect the recalcification time of factor VII-deficient plasma. This suggests that HeLa TCIPA occurs via activation of the extrinsic pathway, probably owing to tumor cell expression of tissue factor-like activity. HeLa cell-induced thrombin generation was confirmed by detection of amidolytic activity towards a chromogenic substrate, S-2238 (H-D-Phe-Pip-Arg-p-NA). Triflavin and GRGDS inhibited, in a dose-dependent manner, TCIPA caused by either cell line. On a molar basis, triflavin was 10,000-30,000 times more potent than GRGDS in this regard. Moreover, monoclonal antibodies raised against glycoprotein (GP) IIb/IIIa complex (i.e., 7E3 and AP2) and against GP Ib (i.e., AP1) completely inhibited HeLa TCIPA. 7E3 and AP2 inhibited B16-F10 TCIPA by up to 80% whereas AP1 showed only 30% inhibition of B16-F10 TCIPA. In conclusion, the inhibitory effect of triflavin on HeLa and B16-F10 TCIPA may be mediated principally by the binding of triflavin to the fibrinogen receptor associated with GP IIb/IIIa complex on the platelet surface. However, GP Ib is also involved in HeLa TCIPA as thrombin formation is the key factor in triggering platelet aggregation caused by HeLa cells.
 ...
PMID:Triflavin, an Arg-Gly-Asp-containing peptide, inhibits tumor cell-induced platelet aggregation. 822 81

As a model system for the identification of genes involved in the progression of human breast cancer, differential gene expression in cell lines MCF-7 and MCF-7ADR was investigated. The latter cell line is derived from the former. Cell line MCF-7 is estrogen receptor-positive, vimentin-negative and uninvasive in the Matrigel outgrowth assay and in the nude mouse, while MCF-7ADR is estrogen receptor-negative, hormone-resistant, vimentin-positive, invasive in the Matrigel outgrowth assay and in the nude mouse and resistant to adriamycin due to overexpression of glycoprotein gp170. We have shown that tumor progression in this model system is mediated by transcriptional regulation of mitochondria-related genes, proteases, transmembrane receptors and cell cycle-related gene proteins. Among the genes differentially regulated at the transcriptional level in the cell lines MCF-7 and MCF-7ADR are a new mitochondrial transcript, mitochondrial creatine kinase, matrix metalloproteinase-1, stromelysin-3, urokinase and its receptor, tissue factor, E-cadherin, epidermal growth factor receptor, transmembrane proteins Mat-8 and progression associated protein (PAP), cyclin E, cyclin-dependent kinase-2 and cell cycle inhibitory proteins p16, p21 and p27.
Clin Exp Metastasis 1998 Feb
PMID:Molecular analysis of two mammary carcinoma cell lines at the transcriptional level as a model system for progression of breast cancer. 951 94


1 2 3 4 5 6 Next >>