Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability

Nobuyuki Akita; Ning Ma; Takayuki Okamoto; Kunihiro Asanuma; Kakunoshin Yoshida; Junji Nishioka; Motomu Shimaoka; Koji Suzuki; Tatsuya Hayashi

doi:10.1016/j.thromres.2015.03.026

Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability

Thromb Res. 2015 Jun;135(6):1203-8. doi: 10.1016/j.thromres.2015.03.026. Epub 2015 Apr 9.

Authors

Nobuyuki Akita¹, Ning Ma², Takayuki Okamoto³, Kunihiro Asanuma⁴, Kakunoshin Yoshida⁴, Junji Nishioka⁵, Motomu Shimaoka³, Koji Suzuki⁶, Tatsuya Hayashi⁷

Affiliations

¹ Faculty of Medical Engineering, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
² Faculty of Health Science, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
³ Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.
⁴ Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.
⁵ Department of Clinical Nutrition, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
⁶ Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
⁷ Department of Biochemistry, Mie Prefectural College of Nursing, Tsu-city, Mie, Japan. Electronic address: tatsuya.hayashi@mcn.ac.jp.

PMID: 25887633
DOI: 10.1016/j.thromres.2015.03.026

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.

Keywords: Neoplasm metastasis; Protein C; Protein C inhibitor; Serine protease inhibitors; Thrombomodulin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Coagulants / chemistry*
Female
Humans
Immunoenzyme Techniques
Immunohistochemistry
Lung Neoplasms / drug therapy*
Male
Melanoma, Experimental
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Metastasis
Neoplasm Transplantation
Protein C / antagonists & inhibitors*
Protein C Inhibitor / blood*
Protein C Inhibitor / chemistry
RNA / analysis
Thrombomodulin / chemistry
Thrombophilia / blood*
Time Factors

Substances

Coagulants
Protein C
Protein C Inhibitor
SERPINA5 protein, human
SERPINA5 protein, mouse
Thrombomodulin
RNA