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 (TF) is aberrantly expressed on tumor vascular endothelial cells (VECs) and on cancer cells in many malignant tumors, but not on normal VECs, making it a promising target for cancer therapy. As a transmembrane receptor for coagulation factor VIIa (fVIIa), TF forms a high-affinity complex with its cognate ligand, which is subsequently internalized through receptor-mediated endocytosis. Accordingly, we developed a method for selectively delivering EF24, a potent synthetic curcumin analog, to TF-expressing tumor vasculature and tumors using fVIIa as a drug carrier. EF24 was chemically conjugated to fVIIa through a tripeptide-chloromethyl ketone. After binding to TF-expressing targets by fVIIa, EF24 will be endocytosed along with the drug carrier and will exert its cytotoxicity. Our results showed that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in a rabbit cornea model and in a Matrigel model in athymic nude mice. The conjugate-induced apoptosis in tumor cells and significantly reduced tumor size in human breast cancer xenografts in athymic nude mice as compared with the unconjugated EF24. By conjugating potent drugs to fVIIa, this targeted drug delivery system has the potential to enhance therapeutic efficacy, while reducing toxic side effects. It may also prove to be useful for treating drug-resistant tumors and micro-metastases in addition to primary tumors.
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PMID:Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa. 1836 80

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

Tissue factor (TF) is a transmembrane glycoprotein cofactor of activated blood coagulation factor VII (FVIIa) that is required for hemostatic thrombin generation at sites of blood vessel injury. Membrane-associated TF detected in circulating blood of healthy subjects, referred to as intravascular or circulating TF has been shown to contribute to experimental thrombus propagation at sites of localized vessel injury. Certain disease states, such as metastatic cancer, are associated with increased levels of intravascular TF and an elevated risk of venous thromboembolism. However, the physiological relevance of circulating TF to hemostasis or thrombosis, as well as cancer metastasis, is ill-defined. This study was designed to assess whether the spatial separation of intravascular TF carriers in blood, demonstrated with TF-inducible human monocytic cell line U937 or TF-coated polymer microspheres, affected procoagulant activity and hence thrombogenic potential. Experiments were performed to characterize the effects of TF-carrier number on the kinetics of clot formation in both open and closed systems. The procoagulant activity of TF carriers was found to correlate with spatial separation in both closed, well-mixed systems and open, flowing systems. TF carriers enhanced the amidolytic activity of FVIIa toward the chromogenic substrate, S-2366, as a function of carrier count. These results suggest that TF-initiated coagulation by circulating TF is kinetically limited by mass transport of TF-dependent coagulation factors to the TF-bearing surface, a constraint that may be unique to circulating TF. Spatial separation of circulating TF carriers is therefore a critical determinant of the procoagulant activity of circulating TF.
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PMID:The role of carrier number on the procoagulant activity of tissue factor in blood and plasma. 2204 20