Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions
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Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan
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Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan
3
Department of Gynecology and Reproductive Medicine, Aska Ladies Clinic, 3-3-17 Kitatomigaoka-cho, Nara 634-0001, Japan
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(9), 1447; https://doi.org/10.3390/cancers17091447
Submission received: 25 February 2025
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Revised: 20 April 2025
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Accepted: 24 April 2025
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Published: 25 April 2025
(This article belongs to the Section Cancer Biomarkers)
Simple Summary
Tissue factor pathway inhibitor 2 (TFPI2) has emerged as a novel serum biomarker for ovarian cancer, gaining insurance coverage in Japan in 2021. Initially characterized as a tumor suppressor gene, TFPI2 exhibits elevated serum levels in patients with ovarian and endometrial cancers compared to healthy individuals, correlating with poor prognostic outcomes. Conventionally, tumor suppressor genes are expected to be downregulated in malignancies; however, clinical observations reveal a paradoxical increase. This review article investigates the role of TFPI2 in both non-malignant and malignant tissues to elucidate the underlying mechanisms of this discrepancy. We aim to raise global awareness among researchers and clinicians regarding the intriguing functions of TFPI2 and to promote its broader clinical application.
Abstract
Objectives: Tissue factor pathway inhibitor 2 (TFPI2) is a serine protease inhibitor that suppresses tumors by preventing extracellular matrix degradation and invasion. In many malignancies, the TFPI2 promoter hypermethylation silences its transcription, increasing tumor aggressiveness. However, TFPI2 paradoxically facilitates tumor progression in certain malignancies. Elevated circulating TFPI2 levels correlate with increased cancer aggressiveness and poor prognosis in ovarian, endometrial, and renal cell carcinoma, though the mechanisms underlying its tumor-promoting effects remain unclear. This review consolidates recent findings on TFPI2 regulation, its downstream targets in cellular homeostasis, and its prognostic significance. Additionally, we reassess TFPI2′s role in tumorigenesis, particularly in clear cell carcinoma, as well as in chronic inflammation. Methods: A comprehensive literature search was performed in PubMed and Google Scholar without time restriction. Results: TFPI2 expression is tightly regulated by transcription factors, signaling molecules, growth factors, cytokines, and epigenetic modification. TFPI2 regulates cell proliferation, inflammation, and extracellular matrix (ECM) remodeling, preserving tissue homeostasis. TFPI2 also regulates vascular endothelial and smooth muscle cell proliferation, key elements of the tumor microenvironment (TME). In the nucleus, it may modulate transcription factors to influence tumor-associated macrophage (TAM) polarization, facilitating cancer invasion. Its expression may be shaped by interactions between cancer cells and TAM activation. Beyond tumorigenesis, TFPI2 contributes to both inflammatory progression and resolution in diabetes, atherosclerosis, and preeclampsia. Conclusions: TFPI2 may interact with TAMs and inflammatory cells to regulate cell proliferation and inflammation, maintaining tissue homeostasis.
