Tissue Factor and Cancer: Regulation, Tumor Growth, and Metastasis

Abstract

There is a strong relationship between tissue factor (TF) and cancer. Many cancer cells express high levels of both full-length TF and alternatively spliced (as) TF. TF expression in cancer is associated with poor prognosis. In this review, the authors summarize the regulation of TF expression in cancer cells and the roles of TF and asTF in tumor growth and metastasis. A variety of different signaling pathways, transcription factors and micro ribonucleic acids regulate TF gene expression in cancer cells. The TF/factor VIIa complex enhances tumor growth by activating protease-activated receptor 2 signaling and by increasing the expression of angiogenic factors, such as vascular endothelial growth factor. AsTF increases tumor growth by enhancing integrin β1 signaling. TF and asTF also contribute to metastasis via multiple thrombin-dependent and independent mechanisms that include protecting tumor cells from natural killer cells. Finally, a novel anticancer therapy is using tumor TF as a target to deliver cytotoxic drugs to the tumor. TF may be useful in diagnosis, prognosis, and treatment of cancer.

Figure 1

Contributions of tumor tissue factor (TF) to tumor growth and metastasis. The tumor TF and factor (F) VIIa complex contributes to tumor growth and metastasis by activating coagulation cascade generating fibrin and by directly and indirectly activating protease activated receptors (PARs). There are negative and positive roles of PAR-1 in tumor growth.

Figure 2

Proposed regulation of tissue factor (TF) expression in cancer cells. Hepatocyte growth factor (HGF)/c-Met and EGFR pathways activate multiple kinase pathways, including c-Jun N-terminal kinase (JNK), Src, phosphatidylinositol-3 kinase (PI3k)/Akt/mammalian target of rapamycin (mTOR), and KRAS/Raf/MEK/ERK. These kinase pathways enhance TF gene expression by expressing transcription factors, such as activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and early growth response protein-1 (Egr-1). TF protein was modified from Servier Medical Art, licensed under Creative Common Attribution 3.0 Unported License. (http://www.servier.fr/servier-medical-art)

Figure 3

Proposed mechanisms of tumor tissue factor (TF) and thrombin-dependent tumor growth. (A) The full-length TF/factor (F) VIIa complex binds to integrin β1 and the TF/FVIIa/ integrin β1 complex activate protease activated receptor (PAR)2. PAR2 activates phosphatidylinositol- 3-kinase (PI3 kinase) and mitogen activated protease (MAP) kinase signalings resulting in tumor growth. (B) Thrombin activates PAR1 that has both positive and negative role in tumor growth. (C) Alternative spliced (as) TF is released from tumor cells and binds to integrin α6β1. This asTF/integrin α6β1complex contributes to tumor growth via PI3 and MAP kinases. Cells and proteins were modified from Servier Medical Art, licensed under Creative Common Attribution 3.0 Unported License. (http://www.servier.fr/servier-medical-art)

Figure 4

Proposed mechanisms of tumor tissue factor (TF)-dependent metastasis. The full-length TF/factor (F)VIIa/FXa complex generates thrombin that activates platelets and generate fibrin. These activated platelets and fibrin inhibit the function of natural killer (NK) cells and attract monocytes/macrophage that helps establishment of premetastatic niche and tumor cell survival in metastatic niche. Cells and proteins were modified from Servier Medical Art, licensed under Creative Common Attribution 3.0 Unported License. (http://www.servier.fr/servier-medical-art)