Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progesterone in hormonal preparations increases the incidence of breast cancer. Tissue factor (TF), the initiator of the extrinsic coagulation pathway, is associated with metastasis in a wide variety of cancers. We demonstrate herein that TF mRNA and protein are up-regulated by progesterone in the breast cancer cell line ZR-75. Epidermal growth factor, also associated with increased breast cancer risk, did not regulate TF. The increase in TF is both rapid and transient; increasing after 6 h, reaching a maximum at 24 h, before decreasing to basal levels at 72 h. Sucrose gradient experiments demonstrated that TF is located in the heavy fraction of the plasma membrane, although caveolin-1 is not expressed in ZR-75. To understand the physiological implications of an increase in TF, we performed coagulation and invasion assays. An increase in TF corresponded to an increase in procoagulant activity. Furthermore, progesterone increased the invasion of ZR-75 cells through a matrigel, an effect that was blocked by an antibody against TF. Because TF expression is associated with an enhanced risk of metastasis, we postulate that the progesterone-dependent up-regulation of TF provides a survival advantage to burgeoning breast cancer cells and may contribute to the increased risk of cancer associated with combined hormone replacement therapy.
 ...
PMID:Progesterone increases tissue factor gene expression, procoagulant activity, and invasion in the breast cancer cell line ZR-75-1. 1556 24

Estrogen and progestin combination in hormone replacement therapy (HRT) increases the incidence of breast cancer, but decreases the endometrial cancer risk of unopposed estrogen. Therefore, a SERM such as Tibolone, that delivers the beneficial, but not the adverse side effects, of steroid hormones would be clinically advantageous. However, data from the Million Women Study suggests that Tibolone increases the risk of both breast and endometrial cancer. Herein, we assessed the estrogenic and progestagenic actions of Tibolone using transvaginal sonography studies and an in vitro model of breast (ZR-75, MCF7) and endometrial cancer (Ishikawa). The known cancer associated proteins (ER, EGFR, STATS, tissue factor and Bcl-xL) were selected for study. Transvaginal sonography demonstrated that postmenopausal women treated with Tibolone displayed a thinner endometrium than in the late proliferative phase, but had a phenotype characteristic of the secretory phase, thus demonstrating the estrogenic and progestagenic actions of this SERM. In vitro, Tibolone acted as an estrogen in downregulating ER and upregulating Bcl-xL, yet as progesterone, increasing STAT5 and tissue factor in breast cancer cells. The increase in tissue factor by Tibolone correlated with its coagulative potential. Interestingly, EGFR was up-regulated by progesterone in the breast and by estrogen in endometrial cells, while Tibolone increased protein levels in both cell types. In conclusion, this study further demonstrates the estrogenic and progestagenic nature of Tibolone. The pattern of regulation of known oncogenes in cells of breast and endometrial origin dictates caution and vigilance in the prescription of Tibolone and subsequent patient monitoring.
 ...
PMID:In vivo and in vitro estrogenic and progestagenic actions of Tibolone. 1623 3

Thrombosis is one of the major complications of malignant disease, but the underlying molecular and cellular basis remains elusive. A number of hypotheses have been put forth, including the expression of tissue factor by tumor cells, release of tissue factor during cell death following chemotherapy, intrinsic unique tumor procoagulants and microparticles. Exploration of a potential role of microparticles in cancer-associated thrombosis indicates that tissue factor microparticles are present in a spectrum of cancer patients known to have a high incidence of thromboembolic complications.
 ...
PMID:Cancer-associated thrombosis. 1649 Mar 69

Progression of human malignancies is accompanied by vascular events, such as formation and remodeling of blood vessels and systemic coagulopathy. Though long appreciated as comorbidity of cancer (Trousseau syndrome), vascular involvement is increasingly recognized as a central pathogenetic mechanism of tumor growth, invasion and metastasis. The major outstanding question in relation to this role has been, whether vascular perturbations are simply a reaction to the conditions of the tumor microenvironment, or are linked to the known genetic lesions causal for the onset and progression of malignancy. In this regard, we have previously hypothesized, and recently demonstrated experimentally that deregulation of certain hemostatic mechanisms, namely upregulation of tissue factor (TF) and possibly other changes (e.g. expression of thrombin receptor - PAR-1) are controlled by cancer-associated oncogenic events, such as activation of K-ras, epidermal growth factor receptor (EGFR), or inactivation of the p53 tumor suppressor gene in various human cancer cells. It appears that these respective transforming alterations exert their impact on both, cell-associated and soluble/circulating (microvesicle- associated) TF, i.e. may cause a systemic hypercoagulable state. Other genes, which more recently emerged as regulators of cancer coagulopathy include: PML-RARalpha, PTEN, and MET. While the spectrum of procoagulant targets of these genes may vary somewhat it includes: TF, PAI-1, COX-2 and possibly other hemostatic proteins. It is noteworthy that these prothrombotic changes may impact the malignant process directly (e.g. stimulate angiogenesis, tumor growth or metastasis) as a consequence of both coagulation-dependent and -independent effects. The latter are mostly related to cellular signaling events and changes in gene expression which are now known to be induced by the TF/FVIIa/Xa complex, thrombin and PARs, expressed on the surface of cancer cells, as well as tumor-associated endothelium. Interestingly, certain anticoagulants possess antimetastatic and anticancer properties (e.g. LMWH), an observation that further suggests that hypercoagulability may act as an effector mechanism of genetically driven tumor progression. Conversely, we suggest that oncogene-directed (targeted) anticancer agents could, at least in some cases, ameliorate not only cellular transformation itself, but also some of the chronic components of the cancer-related coagulopathy, something that may be relevant to therapeutic efficacy of these drugs. We also postulate that since TF is the oncogene target, circulating TF (microparticles) could serve as surrogate marker of the biological activity oncogene-directed agents exert in vivo. Thus, both genetic and epigenetic factors appear to conspire to activate various components of the hemostatic system in cancer patients, both locally and systemically. These activities act as mediators of cancer coagulopathy, angiogenesis, metastasis and other events involved in disease progression and should be recognized in designing better anticancer therapies.
 ...
PMID:Genetic determinants of cancer coagulopathy, angiogenesis and disease progression. 1663 63

Venous thromboembolism (VTE) is a frequent complication in individuals with cancer and is considered to be a cause of substantial mortality. Epidemiological studies identify malignancy as an independent VTE risk factor and show that cancer patients are at increased risk of both initial and recurrent VTE events. The risk due to cancer is compounded by the effects of chemotherapy and other treatments. The pathogenesis of cancer-associated VTE is complex involving multiple interactions between tumours and various components of haemostasis. The development of a systemic hypercoagulable state is considered a key pathogenetic feature and is attributed to tumour expression of tissue factor and other procoagulants, activation of vascular cells by tumour-derived cytokines and adhesive interactions between tumour cells and host cells. An increasing body of evidence indicates that the activation of haemostasis in malignant disease contributes to tumour growth and progression by stimulation of intracellular signalling pathways. The interaction of tissue factor, thrombin and other coagulation factors with protease activated receptor (PAR) proteins expressed by tumour cells and host vascular cells leads to the induction of genes related to the processes of angiogenesis, cell survival and cell adhesion and migration.
 ...
PMID:The pathogenesis of venous thromboembolism in cancer: emerging links with tumour biology. 1678 43

There is strong evidence linking venous thromboembolic events and malignancy. Laboratory markers of coagulation activation such as thrombin-antithrombin complex or prothrombin fragments 1+2 support the premise that malignancy is a hypercoagulable state. Inflammatory cytokines (e.g. tumor necrosis factor and interferon-gamma), coagulation proteins (e.g. tissue factor and factor VIII), and procoagulant microparticles may be elevated in patients with malignancy. However, the molecular basis for cancer associated thrombosis remains unknown and the relative contribution of chemotherapeutics, tumor cells, endothelium, and circulating procoagulants in promoting thrombus formation continues to be investigated.
 ...
PMID:Cancer-associated thrombosis. 1729 22

Coagulation activation by tissue factor (TF) is implicated in cancer progression, cancer-associated thrombosis and metastasis. The role of direct TF signaling pathways in cancer, however, remains incompletely understood. Here we address how TF contributes to primary tumor growth by using a unique pair of isotype-matched antibodies that inhibit either coagulation (monoclonal antibody [Mab]-5G9) or direct signaling (Mab-10H10). We demonstrate that the inhibitory antibody of direct TF-VIIa signaling not only blocks TF-VIIa mediated activation of PAR2, but also disrupts the interaction of TF with integrins. In epithelial and TF-expressing endothelial cells, association of TF with beta1 integrins is regulated by TF extracellular ligand binding and independent of PAR2 signaling or proteolytic activity of VIIa. In contrast, alpha3beta1 integrin association of TF is constitutive in breast cancer cells and blocked by Mab-10H10 but not by Mab-5G9. Mab-5G9 has antitumor activity in vivo, but we show here that Mab-10H10 is at least as effective in suppressing human xenograft tumors in 2 different models. Breast tumor growth was also attenuated by blocking PAR2 signaling. These results show that tumor cell TF-PAR2 signaling is crucial for tumor growth and suggest that anti-TF strategies can be applied in cancer therapy with minor impairment of TF-dependent hemostatic pathways.
 ...
PMID:Inhibition of tissue factor signaling suppresses tumor growth. 1790 Dec 45

Venous thromboembolism (VTE) is a well-recognized problem in malignancy. Patients with cancer who have VTE have a worse prognosis than other patients with cancer. Hypercoagulability in patients with cancer is related to malignancy itself and its treatment. These patients have multiple risk factors for thromboembolism, such as being immobilized, having central venous catheters, and receiving chemoradiation therapy. Cancer procoagulant, tissue factor, factor VIII, and thrombin have important roles in causing cancer-associated thromboembolism. Tumors require neovascularization for delivering oxygen and other nutrients. Therefore, angiogenesis facilitates tumor growth, invasion, and metastasis. New blood vessels formed by angiogenesis are thrombogenic. Hypercoagulability and tumor growth are closely related. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that may also cause VTE in patients with cancer. The relationship between cancer, angiogenesis, VEGF, and thrombosis is reviewed herein. Studies are ongoing to enhance our understanding of this complex interaction.
 ...
PMID:Venous thromboembolism in patients with cancer and its relationship to the coagulation cascade and vascular endothelial growth factor. 1863 33

Blood-borne tissue factor (TF)-bearing microparticles have been shown to play an important role in thrombus propagation in experimental models. The pathophysiologic role of these microparticles is being investigated in several prothrombotic conditions including cancer-associated thrombosis. Tumor cells are known to shed TF-bearing microparticles in vitro, and circulating TF-bearing microparticles can be measured in plasma samples from patients with advanced cancer. We are currently using an impedance-based flow cytometer to accurately size and enumerate TF-bearing microparticles to explore the association between cancer thrombosis and elevations in circulating TF-bearing microparticles.
 ...
PMID:Tissue factor-bearing microparticles and cancer. 1864 25

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.
 ...
PMID:Platelet-derived microparticles and coagulation activation in breast cancer patients. 1884 Dec 90


1 2 3 4 5 6 7 Next >>