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.
目的：组织因子途径抑制物2（TFPI2）是一种丝氨酸蛋白酶抑制剂，通过抑制细胞外基质降解和肿瘤侵袭发挥抑癌作用。在多种恶性肿瘤中，TFPI2启动子高甲基化可沉默其转录，从而增强肿瘤侵袭性。然而矛盾的是，在某些恶性肿瘤中TFPI2反而促进肿瘤进展。循环TFPI2水平升高与卵巢癌、子宫内膜癌和肾细胞癌的肿瘤侵袭性增强及不良预后相关，但其促肿瘤作用的具体机制尚未明确。本综述整合了TFPI2调控机制、其在细胞稳态中的下游靶点及预后意义的最新研究进展，并重新评估了TFPI2在肿瘤发生（特别是透明细胞癌）及慢性炎症中的作用。方法：在PubMed和Google Scholar数据库进行无时间限制的文献系统检索。结果：TFPI2表达受转录因子、信号分子、生长因子、细胞因子及表观遗传修饰的严格调控。TFPI2通过调控细胞增殖、炎症反应和细胞外基质重塑维持组织稳态，同时调节血管内皮细胞和平滑肌细胞增殖——这些是肿瘤微环境的关键组分。在细胞核内，TFPI2可能通过调控转录因子影响肿瘤相关巨噬细胞极化，促进癌症侵袭。其表达水平可能受癌细胞与肿瘤相关巨噬细胞激活相互作用的调控。除肿瘤发生外，TFPI2在糖尿病、动脉粥样硬化和子痫前期等疾病中同时参与炎症进展与消退过程。结论：TFPI2可能通过与肿瘤相关巨噬细胞及炎症细胞的相互作用，调控细胞增殖和炎症反应，从而维持组织稳态。
Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions
肿瘤(癌症)患者之家