Abstract
Clotting activation occurs frequently in cancer. Tissue factor (TF), the most potent
initiator of coagulation, is expressed aberrantly in many types of malignancy and
is involved not only in tumor-associated hypercoagulability but also in promoting
tumor angiogenesis and metastasis via coagulation-dependent and coagulation-independent
(signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) is the natural inhibitor
of TF coagulant and signaling activities. Studies have shown that TFPI exhibits antiangiogenic
and antimetastatic effects in vitro and in vivo. In animal models of experimental
metastasis, both circulating and tumor cell-associated TFPI are shown to significantly
reduce tumor cell-induced coagulation activation and lung metastasis. Heparins and
heparin derivatives, which induce the release of TFPI from the vascular endothelium,
also exhibit antitumor effects, and TFPI may contribute significantly to those effects.
Indeed, a non-anticoagulant low-molecular-weight heparin with intact TFPI-releasing
capacity has been shown to have significant antimetastatic effect in a similar experimental
mouse model. The evidence supporting the dual inhibitory functions on TF-driven coagulation
and signaling strengthen the rationale for considering TFPI as a potential anticancer
agent. This article primarily summarizes the evidence for antiangiogenic and antimetastatic
effects of TFPI and describes its potential mechanisms of action. The possible application
of TFPI and other inhibitors of TF as potential anticancer agents is described, and
information regarding potential antitumor properties of TFPI-2 (which has structural
similarities to TFPI) is also included.
Keywords
Tissue factor pathway inhibitor - cancer - metastasis - angiogenesis - tissue factor
