Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

✍ Scribed by Kunihiro Asanuma; Tomoaki Yoshikawa; Tatsuya Hayashi; Nobuyuki Akita; Norimi Nakagawa; Yasuhiko Hamada; Junji Nishioka; Haruhiko Kamada; Esteban C. Gabazza; Masaru Ido; Atsumasa Uchida; Koji Suzuki

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: French
• Weight: 739 KB
• Volume: 121
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.22773

✦ Synopsis

Abstract

Protein C inhibitor (PCI) regulates the anticoagulant protein C pathway and also inhibits urinary plasminogen activator (uPA), a mediator of tumor cell invasion. In the present study, we evaluated the effect of human PCI and its inactive derivatives on tumor growth and metastasis of human breast cancer (MDA‐231) cells, and on angiogenesis in vivo. The invasiveness of MDA‐231 cells was inhibited by recombinant intact PCI, but not by reactive site‐modified PCI (R354APCI) or by the N‐terminal fragment of protease‐cleaved PCI (NTPCI). The in vitro invasiveness of MDA‐231 cells expressing intact PCI (MDA‐PCI) was significantly decreased as compared to MDA‐231 cells expressing R354APCI (MDA‐R354APCI) or NTPCI (MDA‐NTPCI). Further, in vivo growth and metastatic potential of MDA‐PCI, MDA‐R354APCI and MDA‐NTPCI cells in severe combined immunodeficient (SCID) mice were significantly decreased as compared to MDA‐Mock cells. Angiogenesis was also significantly decreased in Matrigel implant containing MDA‐PCI, MDA‐R354APCI or MDA‐NTPCI cells as compared to that containing MDA‐Mock cells. In vivo angiogenesis in rat cornea and in vitro tube formation were also inhibited by recombinant intact PCI, R354APCI and NTPCI. Furthermore, the anti‐angiogenic activity of PCI was strong as cleaved antithrombin (AT), and slightly stronger than that of plasminogen activator inhibitor (PAI)‐1 and pigment epithelium‐derived factor (PEDF). Overall, this study showed that, in addition to a reactive site‐dependent mechanism, PCI may also regulate tumor growth and metastasis independently of its protease inhibitory activity by inhibiting angiogenesis. © 2007 Wiley‐Liss, Inc.