Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability. Issue 6 (June 2015)

• Record Type: Journal Article
• Authors: Akita, Nobuyuki; Ma, Ning; Okamoto, Takayuki; Asanuma, Kunihiro; Yoshida, Kakunoshin; Nishioka, Junji; Shimaoka, Motomu; Suzuki, Koji; Hayashi, Tatsuya
• Is Part Of: Thrombosis research. Volume 135:Issue 6(2015)
• Page Start: 1203
• Page End: 1208
• Publication Date: 2015-06
• Subjects: Protein C inhibitor -- Serine protease inhibitors -- Neoplasm metastasis -- Protein C -- Thrombomodulin; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2015.03.026
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Introduction: Protein C inhibitor (PCI), a member of the serine protease inhibitor family, is expressed in various human tissues, including liver and kidneys. In the plasma, PCI physiologically inhibits an anticoagulant serine protease, activated protein C (APC). PCI expressed by cancer cells suppresses tumor invasion by inhibiting urokinase-type plasminogen activator, and inhibits tumor growth and metastasis, which are independent of its protease-inhibitory activity. In the present study, we clarified the effects of host PCI on growth and metastasis of B16 melanoma (B16) cells by comparing between wild-type mice and mice transgenic for human PCI gene (hPCI-TG), which have a tissue distribution of PCI similar to that observed in humans. Materials and Methods: Growth of intracutaneously-injected B16 cells was evaluated by measuring the tumor volume, and metastatic behavior of intravenously-injected B16 cells by counting the number of metastatic lung nodules. Results: Growth of intracutaneously injected B16 cells was significantly faster in wild-type mice than in hPCI-TG mice; however, hPCI-TG mice developed more metastatic nodules of B16 cells in the lungs. Immunohistochemical analysis using anti-mouse fibrinogen antibody revealed more fibrin deposition in the lung in hPCI-TG mice than in wild-type mice. Furthermore, the more invasive behavior observed in hPCI-TG mice was reduced by rabbit anti-human PCI IgG, APC, or soluble TM administration for 3 consecutive days including the day that B16 cells were injected. Conclusions: Our results suggest that like PCI expressed in tumor cells, host PCI also inhibits tumor growth, but host PCI promotes tumor metastasis via its procoagulant properties. Highlights: Tumor cell growth is suppressed by PCI in plasma. Tumor cell metastasis is promoted by PCI in plasma. The enhancement of metastatic ability is by the procoagulant nature of PCI.