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Review
. 2024 Dec;43(4):1185-1204.
doi: 10.1007/s10555-024-10205-7. Epub 2024 Aug 17.

Tissue factor pathway inhibitor-2 (TFPI-2)-an underappreciated partaker in cancer and metastasis

Marek Z Wojtukiewicz #  1   2 , Marta Mysliwiec #  3 , Anna Tokajuk  4 , Joanna Kruszewska  3 , Barbara Politynska  5   6 , Anmbreen Jamroze  7 , Anna M Wojtukiewicz  5 , Dean G Tang  7 , Kenneth V Honn  8   9   10
Affiliations
Review

Tissue factor pathway inhibitor-2 (TFPI-2)-an underappreciated partaker in cancer and metastasis

Marek Z Wojtukiewicz et al. Cancer Metastasis Rev. 2024 Dec.

Abstract

The coagulation system is known to play an important role in cancer development and metastasis, but the precise mechanisms by which it does so remain incompletely understood. With this in mind, we provide an updated overview of the effects of TFPI-2, a protease inhibitor, on cancer development and metastasis. TFPI-2 interacts with the thrombin cascade and also employs other mechanisms to suppress cancer growth and dissemination, which include extracellular matrix stabilization, promotion of caspase-mediated cell apoptosis, inhibition of angiogenesis and transduction of intracellular signals. Down-regulation of TFPI-2 expression is well documented in numerous types of neoplasms, mainly via promoter methylation. However, the exact role of TFPI-2 in cancer progression and possible approaches to up-regulate TFPI-2 expression warrant further studies. Strategies to reactivate TFPI-2 may represent a promising direction for future anticancer studies and therapy development.

Keywords: Cancer; Coagulation; Hemostasis; Metastasis; Tissue factor pathway inhibitor; Tumor.

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Conflict of interest statement

Declarations Ethical Approval Not applicable (review paper). Competing interests The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Regulators of TFPI-2 expression and function. Red boxes represent compounds that downregulate TFPI-2 expression or function, while green boxes represent compounds that upregulate TFPI-2 expression or function. Created with BioRender.com. (COX-2—cyclooxygenase-2; EZH2—zeste homolog 2; FTO—fat mass and obesity-related protein; lncRNAs—long non-coding RNAs; LSD1—lysine specific demethylase 1; LSD2—lysine specific demethylase 2; MAFB—musculo-aponeurotic fibrosarcoma oncogene homolog B; MAPK—mitogen-activated protein kinase; MBD3—methyl-CpG binding domain protein 3; MEG8—maternally expressed gene 8; miRNAs—microRNA; PARP1—Poly (ADP-ribose) polymerase; RARα—retinoid acid receptor α; VEG—vascular endothelial growth factor)
Fig. 2
Fig. 2
Interaction of TFPI-2 with blood coagulation. Versatile sources of TFPI-2 protein include endothelial cells, platelets, macrophages, and cancer cells. Created with BioRender.com. (COX-2—cyclooxygenase-2; ECs—endothelial cells; fVIIa—factor VIIa; fXIa—factor XIa; MAPK—mitogen-activated protein kinase; PAR-1—protease-activated receptor-1; TF—tissue factor; TFPI-2—Tissue factor pathway inhibitor-2; VEGF—vascular endothelial growth factor
Fig. 3
Fig. 3
Mechanisms of TFPI-2 interaction with cancer. Created with BioRender.com. (EMT—epithelial-mesenchymal transition; ERK—extracellular signal-regulated kinase; MEG8—Maternally Expressed Gene 8; MMP-1—matrix metalloproteinases 1; MMP-9—matrix metalloproteinases 9; PSAP—prosaposin; SMAD—Mothers against decapentaplegic; TF—tissue factor; TFPI-2—Tissue factor pathway inhibitor-2; TGFB—transforming growth factor beta; TMPRSS4—transmembrane protease serine 4; TWIST1—Twist-related protein 1; VEGF—vascular endothelial growth factor)
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