Functional Characteristics and Regulated Expression of Alternatively Spliced Tissue Factor: An Update

Abstract

In human and mouse, alternative splicing of tissue factor’s primary transcript yields two mRNA species: one features all six TF exons and encodes full-length tissue factor (flTF), and the other lacks exon 5 and encodes alternatively spliced tissue factor (asTF). flTF, which is oftentimes referred to as “TF”, is an integral membrane glycoprotein due to the presence of an alpha-helical domain in its C-terminus, while asTF is soluble due to the frameshift resulting from the joining of exon 4 directly to exon 6. In this review, we focus on asTF—the more recently discovered isoform of TF that appears to significantly contribute to the pathobiology of several solid malignancies. There is currently a consensus in the field that asTF, while dispensable to normal hemostasis, can activate a subset of integrins on benign and malignant cells and promote outside-in signaling eliciting angiogenesis; cancer cell proliferation, migration, and invasion; and monocyte recruitment. We provide a general overview of the pioneering, as well as more recent, asTF research; discuss the current concepts of how asTF contributes to cancer progression; and open a conversation about the emerging utility of asTF as a biomarker and a therapeutic target.

Tissue factor as a new target for tumor therapy—killing two birds with one stone: a narrative review

“…The TF expressed at the protein level includes two isoforms: the membrane-bound full-length TF (flTF) and the soluble alternatively spliced TF (asTF). AsTF plays a vital role in angiogenesis with the assistance of integrin β1 and β3 ( 23 , 24 ), and influences tumor invasion and metastasis processes ( 25 , 26 ). FlTF triggers protease-activated receptors (PARs) that affect tumor cell behavior and regulates the function of integrin, which has an independent role in coagulation ( 27 ).…”

Plasma tissue factor activity in lung cancer patients predicts venous thromboembolism and poor overall survival

“…Full-length TF, released by activated cells [ 25 ], circulates associated with extracellular vesicles (EVs) and, if not encrypted [ 26 ], has a potent procoagulant activity. Alternatively, spliced TF has little to no procoagulant activity but plays a role in neoangiogenesis and cancer progression by interactions with integrins [ 27 ].…”

Evaluation of four commercial ELISAs to measure tissue factor in human plasma

“…Another challenge with antigen-based assays is that TF can be present in both active and inactive forms [ 5 ]. Although the majority of TF in plasma and cell culture supernatants is associated with EVs [ 6 , 7 ], an alternatively spliced form of TF (asTF) can be expressed that is soluble but has low procoagulant activity compared to full-length TF [ [8] , [9] , [10] ].…”