HSA-TIMP-2 (Angiolab)

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.

The aim was to evaluate the potential role of tissue factor pathway inhibitor-2 (TFPI-2) in the process of malignant transformation of sinonasal inverted papilloma (SIP). We evaluated the expression of TFPI-2 in 23 SIP and 8 SIP with squamous cell carcinoma (IPcSCC), compared to 9 normal sinonasal mucosa by means of Western blot and immunohistochemistry staining. In addition, angiogenesis, vascular endothelial growth factor (VEGF) expression and microvessel density marked by CD105 staining were assessed. Correlation of TFPI-2 expression and angiogenesis in the process of malignant transformation of SIP was investigated. Western blot results demonstrated that the protein level of TFPI-2 in IPcSCC was significantly lower than that in the control group (P < 0.01). In addition, significant difference in TFPI-2 protein expression between SIP and IPcSCC was detected (P < 0.01). Higher number of microvessel per unit area (MVNA) was observed in IPcSCC compared to SIP (P < 0.01). Correlational analysis indicated positive correlation of VEGF and MVNA (r = 0.735), inverse correlation of TFPI-2 and MVNA (r = -0.318). However, no significant correlation between TFPI-2 and VEGF was detected. We conclude that TFPI-2 might be a regulatory molecule in the malignant potential of SIP. Down regulation of TFPI-2 is associated with increased MVNA in IPcSCC, which may be involved in the process of malignant transformation of SIP.