Fig. 4

This text discusses the formation and role of flTF and asTF in carcinogenesis, as well as the roles of flTF -VIIa in the growth, invasion, and metastasis of cancer cells. The binding of TF to SR leads to the formation of asTF, while lack of binding leads to the formation of flTF. On the one hand, asTF increases cell cycle proteins (CNNA1/2 and ANAPC10), growth factors (MDK, TIMP-1, Gal), and factors involved in positive integrin regulation (FERMT2), while decreasing factors involved in negative integrin regulation (TENSIN3). Furthermore, binding to integrins α6β1 and β3vα leads to PAR2-independent signaling and consequently increased tumor cell metastasis. Decreased phosphorylation of SRP55 and ASF/SF2 following TOPOI inhibition leads to increased asTF expression and production, while miR126 results in decreased asTF expression and production. The binding of flTF to integrin α3β1 and increased PAR2 expression leads to increased VEGF, IL8, and CXCL1 expression, angiogenesis, and increased tumor cell metastasis. miR19a decreases flTF production and expression. flTF-VIIa plays a role in carcinogenesis in several ways: 1) increasing UPAR expression and consequently tumor cell invasion, 2) phosphorylation and activation of AKT following PAR2 activation, which results in the conversion of inactive Rab-GDP to active Rab-GTP, actin polymerization, and release of microvesicles (MV), ultimately resulting in tumor cell invasion and metastasis, and 3) increasing cancer cell growth following activation of the P42-P44 MAPK, PI3K/AKT, RAS/RAF/MEK/ERK, and SRC-like kinase signaling pathways. flTF, via binding to ABP-280, which is itself activated by TNF-α and lysophosphatidic acid (LPA), can activate the aforementioned signaling pathways. The flTF-VIIa complex, binding to factor Xa, leads to PAR2 cleavage and activation of endothelial cells. Factor Xa, trypsin 1/2/4, kallikreins 2/4/6/14, elastase, protease 3, and cathepsins G/S activate PAR2, while thrombin, Xa, and APC cleave and activate PAR1, which all act in favor of tumor progression and invasion