Tissue Factor (TF) is an evolutionary conserved glycoprotein, which is of immense importance for a variety of biologic processes. TF is expressed in two naturally occurring protein isoforms, membrane-bound "full-length" (fl)TF and soluble alternatively spliced (as)TF. The TF isoform expression is differentially modulated on post-transcriptional level via regulatory factors, such as serine/arginine-rich (SR) proteins, SR protein kinases and micro (mi)RNAs. Both isoforms mediate a variety of physiologic-and pathophysiologic-relevant functions, such as thrombogenicity, angiogenesis, cell signaling, tumor cell proliferation and metastasis. In this review, we will depict the main mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Moreover, we will summarize and discuss the latest findings regarding the role of TF and its isoforms in cancer biology.Tissue factor (TF) is a glycoprotein and an evolutionary conserved member of the Class II cytokine receptor family, which was found in different species, such as human, mouse, rat, fish as well as in Drosophila melanogaster and mosquitos. 1-3 TF is expressed in two natural occurring protein isoforms, full-length (fl)TF and alternatively spliced (as)TF. [4][5][6] In human, flTF consists of a short intracellular domain (21 amino acids), a transmembrane domain (23 amino acids) and an extracellular domain (219 amino acids). 7 flTF is anchored to the cell membrane. 7,8 The primary function of flTF is the initiation of the blood coagulation cascade. 2,7,8 Beside this, flTF plays an important role in a variety of other biological processes, such as protease-activated receptor (PAR-)2-mediated cell signaling and tumor progression. 2,9,10 Due to alternative splicing the fifth exon of the primary TF transcript is excluded. 5,7 Translation of this messenger (m)RNA splice variant leads to the generation of asTF on protein level. asTF lacks the transmembrane domain and is therefore soluble. 7 Compared with flTF, asTF exhibits low prothrombogenic potential. 4,7,8 However, this isoform was recently linked more closely to angiogenesis, survival and cell growth. 3,[11][12][13][14] Post-transcriptional expression control regulate a variety of biologic functions, such as tumor cell invasion, metastasis and angiogenesis in cancer as well as in other settings. [15][16][17][18] Two major mechanisms modulate post-transcriptional expression: micro (mi)RNAs and alternative splicing processes. 16 In this review, we will discuss the latest findings regarding the impact of TF and its isoforms on cancer biology with special focus on pathophysiologic-relevant functions, such as thrombogenicity, tumor cell growth and angiogenesis. Moreover, we will shed light on the mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions.
Cancer-Related Stimulation of TF ExpressionSeveral stimuli, such as hypoxia, vascular endothelial growth factor (VEGF) and the proinflammatory cytokine tumor necrosis fact...
