Research progress on effects of TFPI-2 on proliferation, apoptosis, and metastasis of malignant tumors cells

Tissue factor pathway inhibitor-2 (TFPI-2), a member of the Kunitz-type family, is a broad-spectrum serine proteinase inhibitor. The expression of TFPI-2 is inversely related to increasing degree of malignancy, suggesting a role of TFPI-2 in the mainte- nance of tumor stability and inhibition of the growth of neoplasma. Aberrant methylation of TFPI-2 promoter cytosine-phosphorothio- ate- guanine (CpG) islands has been widely documented to be responsible for diminished expression of TFPI-2 mRNA and protein dur- ing cancer progression. TFPI-2 expression is significantly up-regulated by the ERK1/2 and JNK signaling pathways and modestly in- creased by VEGF, TNF-alpha, and fibroblast growth factor in time- and dose-dependent manners. TFPI-2 can maintain the stability of the tumor environment and inhibit invasiveness and growth of neoplasms. TFPI-2 has also been shown to regulate proliferation, apopto- sis, and vasculogenic mimicry of tumor cells, which may contribute significantly to tumor growth inhibition. Restoration of TFPI-2 ex- pression in tumor tissue inhibits tumor growth and metastasis, which creates a novel possibility of cancer patient treatment. This review focuses on the expression and the molecular regulation mechanisms of TFPI-2 in malignant tumors that control the functions of TFPI-2 in proliferation, apoptosis, and angiogenesis. Insight into these processes will improve our understanding of TFPI-2 and provide new ap- proaches for rational treatment strategies.