Toward an understanding of tissue factor pathway inhibitor-2 as a novel serodiagnostic marker for clear cell carcinoma of the ovary.

Abstract

Tissue factor pathway inhibitor (TFPI)-2 has recently emerged as a serodiagnostic marker for patients with epithelial ovarian cancer (EOC), especially clear cell carcinoma (CCC). This review discusses the biological properties of TFPI-2 and why serum levels are elevated in CCC patients. A comprehensive literature search was conducted in PubMed up until March, 2021. TFPI-2 is a Kunitz-type protease inhibitor and negatively regulates the enzymatic activities, such as plasmin. TFPI-2 has been characterized as a tumor suppressor gene and was frequently downregulated through promoter hypermethylation in various human cancers. In contrast, TFPI-2 was overexpressed only in CCC. TFPI-2 may be involved in the pathophysiology of CCC, possibly through regulation of coagulation system, stabilization of extracellular matrix (ECM), and induction of intracellular signal transduction. TFPI-2 suppresses tissue factor-induced hypercoagulation in a hypoxic environment. TFPI-2, secreted by CCC cells, platelets, and adjacent vascular endothelial cells, may suppress tumor growth and invasion through ECM remodeling. Nuclear TFPI-2 may suppress matrix metalloproteinase production via transcription factors and modulate caspase-mediated cell apoptosis. CCC cells may upregulate the TFPI-2 expression to adapt to survival in the demanding environment. TFPI-2 is secreted by CCC cells and enters the systemic circulation, resulting in elevated blood levels. Serum TFPI-2 reflects the overexpression of TFPI-2 in CCC tissues and is a potential serodiagnostic marker. Further research is needed to explore the expression, clinical significance, biological function, and potential mechanism of TFPI-2 in CCC.