The Tissue Factor Pathway in Cancer: Overview and Role of Heparan Sulfate Proteoglycans

Abstract

Historically, the only focus on tissue factor (TF) in clinical pathophysiology has been on its function as the initiation of the extrinsic coagulation cascade. This obsolete vessel-wall TF dogma is now being challenged by the findings that TF circulates throughout the body as a soluble form, a cell-associated protein, and a binding microparticle. Furthermore, it has been observed that TF is expressed by various cell types, including T-lymphocytes and platelets, and that certain pathological situations, such as chronic and acute inflammatory states, and cancer, may increase its expression and activity. Transmembrane G protein-coupled protease-activated receptors can be proteolytically cleaved by the TF:FVIIa complex that develops when TF binds to Factor VII (PARs). The TF:FVIIa complex can activate integrins, receptor tyrosine kinases (RTKs), and PARs in addition to PARs. Cancer cells use these signaling pathways to promote cell division, angiogenesis, metastasis, and the maintenance of cancer stem-like cells. Proteoglycans play a crucial role in the biochemical and mechanical properties of the cellular extracellular matrix, where they control cellular behavior via interacting with transmembrane receptors. For TFPI.fXa complexes, heparan sulfate proteoglycans (HSPGs) may serve as the primary receptor for uptake and degradation. The regulation of TF expression, TF signaling mechanisms, their pathogenic effects, and their therapeutic targeting in cancer are all covered in detail here.

Long Non-Coding RNAs in Venous Thromboembolism: Where Do We Stand?

“…Beyond cancer-induced hypercoagulability, dysregulation of TF-associated signalling pathways and their constituents play an important role in tumour progression, particularly by impacting angiogenesis and tumour invasion. While TF shows tumour-enhancing characteristics, its natural inhibitors, TFPI1 and TFPI2, are associated with tumour-suppressing properties [154].…”

Revisiting the Syndecans: Master Signaling Regulators with Prognostic and Targetable Therapeutic Values in Breast Carcinoma

“…These findings are relevant given the importance of coagulation disorders in breast cancer patients. Additionally, this study revealed that the removal of HS chains from the SDC3 did not promote the release of TFPI in these cells, suggesting that SDC3-TFPI binding is not dependent on HS attached to SDC3 [ 43 , 44 ]. In another work, Wu and collaborators failed to show a correlation between SDC3 expression in breast carcinoma and lymph node metastasis [ 45 ].…”

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

“…Several excellent reviews on extracellular and cell surface HS–PGs exist in the literature. The interested reader is referred to these for further information [ 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 ]. In this review, the more important aspects of HS interactive components with representative examples of HS–PGs, such as perlecan and the syndecan, will be covered.…”