Tissue factor (coagulation factor III): a potential double-edge molecule to be targeted and re-targeted toward cancer

Abstract

Tissue factor (TF) is a protein that plays a critical role in blood clotting, but recent research has also shown its involvement in cancer development and progression. Herein, we provide an overview of the structure of TF and its involvement in signaling pathways that promote cancer cell proliferation and survival, such as the PI3K/AKT and MAPK pathways. TF overexpression is associated with increased tumor aggressiveness and poor prognosis in various cancers. The review also explores TF's role in promoting cancer cell metastasis, angiogenesis, and venous thromboembolism (VTE). Of note, various TF-targeted therapies, including monoclonal antibodies, small molecule inhibitors, and immunotherapies have been developed, and preclinical and clinical studies demonstrating the efficacy of these therapies in various cancer types are now being evaluated. The potential for re-targeting TF toward cancer cells using TF-conjugated nanoparticles, which have shown promising results in preclinical studies is another intriguing approach in the path of cancer treatment. Although there are still many challenges, TF could possibly be a potential molecule to be used for further cancer therapy as some TF-targeted therapies like Seagen and Genmab's tisotumab vedotin have gained FDA approval for treatment of cervical cancer. Overall, based on the overviewed studies, this review article provides an in-depth overview of the crucial role that TF plays in cancer development and progression, and emphasizes the potential of TF-targeted and re-targeted therapies as potential approaches for the treatment of cancer.

Keywords: Angiogenesis; Cancer; Metastasis; Re-Targeted therapy; Targeted therapy; Tissue factor.

Fig. 1

A schematic representation of the mRNA splicing products of F3 gene is shown. F3 gene, encodes six exons that form open reading frames; five introns are removed during mRNA processing. Three distinct mRNA products are produced, each of which contains coding sequences. By alternative splicing exon 5 is excluded, which results in the production of TF with a shorter length (238 aa) compared to flTF (295 aa). TF-A is a newly identified transcript of the TF gene that is produced by an alternative splicing mechanism involving the first intron. This process causes the incorporation of a sequence from the first intron known as exon IA into the transcript. Moreover, there is a mutation map of F3 gene, showcasing the mutation spots (Produced by www.cbioportal.org). TF: tissue factor; aa: amino acid; asTF; alternatively spliced TF; flTF: full-length TF; TF-A: alternative exon 1A-tissue factor; TM domain: Transmembrane domain

Fig. 2

A Integrins: The binding of TF-FVIIa to integrin leads turning to a high-affinity condition for these molecules. This complex formation is independent of TF-FVIIa potency for cleaving PAR. B Ephs: TF-FVIIa binary complex can cleave both Eph B 2/ A 2 proteolytically; then, signal transduction is induced by ephrins. C JAK-STAT Proteolytic activity of FVIIa causes initiating of apoptosis-related signaling events such as activation of PI3K, Akt, by STAT5 phosphorylation. D 1-Function of the MAP Kinase and PI3K-PKB pathways due to the TF-FVIIa interaction through activating specific transcription factors in the nucleus leads to the gene expression and translation of the synthesized m RNA. D 2-The signaling pathway is activated by a binary complex that consists SRC-like family, PI3K, PKB, and Rac stimulation conducts cytoskeletal rearrangement

Fig. 3

Overview on factors affecting F3 gene and TF-involved signaling pathways progressing cancer. The right and bottom parts of the figure show the positive and negative effectors affecting the expression of TF gene, with blue arrows indicating positive effectors and red arrows indicating negative effectors. Activation of the mTOR pathway, inflammatory cytokines such as TNF, activation of proto-oncogenes such as KRAS, inactivation of PTEN and P53, growth factors such as EGF, FGF and VEGF, and hypoxia are positive effectors. On the other hand microRNAs such as miR19 and miR19a are negative effectors of the expression of TF gene. The top part of the figure shows how TF works in angiogenesis, invasion, metastasis, tumor cell growth, and carcinogenesis. On the one hand, TF leads to uncontrolled growth of cancer cells by activating the JAK2-STAT5 pathway, which prevents the apoptosis of cancer cells, and on the other hand, by activating RTKs, it promotes the growth of tumor cells. TF leads to increased angiogenesis and metastasis of tumor cells by increasing VEGF and inhibiting TSP. TF activates rac1, which in turn activates PKA and regulates MAPK, leading to the growth and metastasis of cancer cells. TF activates PAR2, which in turn leads to increased angiogenesis, invasion, and metastasis of cancer cells in several ways. On the one hand, it leads to increased VEGF, bEGF, IL8, and βTGF- and, therefore angiogenesis, invasion, and metastasis of tumor cells. Moreover, it stabilizes β-catenin and causes invasion of tumor cells. PAR2 also activates MAPK and ERK1/2 pathways, and increases β-arrestin, which phosphorylates cofilin, leading to the polymerization of actin filaments at the edge of invading cells and thus increasing invasion and metastasis of tumor cells. TF activates the signaling pathways PI3K/AKT, MAPK, and FAK by binding to integrins α6β1 and β3vα

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