Abstract
Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1) and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases.
Highlights
Tissue factor (TF) is a 47-kDa membrane-bound cell surface receptor [1,2,3]
In angiogenesis-dependent diseases, notably solid cancers, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA), tissue factor (TF) is selectively expressed on angiogenic vascular endothelial cells (VECs) in the pathological neovasculature
TF is overexpressed by cancer stem cells and by the cancer cells, including solid cancer cells, acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) leukemic cells and sarcoma cells
Summary
Tissue factor (TF) is a 47-kDa membrane-bound cell surface receptor [1,2,3]. It is known as thromboplastin, coagulation factor III (fIII) or CD142. Antibodies 2018, 6, 8 and sequestered from and circulating the in natural ligand for TF.vessel In these cells, pericytes, fibroblasts smoothcoagulation muscle cells,factor whichVII are(fVII), localized the sub-endothelial wall the majority of TF is localized in intracellular pools [4]. Upon disruption of vessel wall integrity, and sequestered from circulating coagulation factor VII (fVII), the natural ligand for TF In these in pericytes and smoothofmuscle is released and can be pools bound[4]. TF in pericytes and smooth muscle cells is released and can be bound by fVII, leaking from of coagulation, TF is a modulator of pathological angiogenesis [7,8,9].[5,6] It is Besides worth noting there blood circulation, to initiate blood coagulation in order to stop bleeding its rolethat as the is primary a truncated version of TF, called spliced. TF is (VEGF)-stimulated human for microvascular endothelial cells (HMVEC)
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