title: Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Faculty of Medical Engineering, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Akita
authors.affiliation: Faculty of Health Science, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Asanuma
authors.affiliation: Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.
authors.forename: Kakunoshin
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Clinical Nutrition, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Nishioka
authors.affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
authors.affiliation: Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Biochemistry, Mie Prefectural College of Nursing, Tsu-city, Mie, Japan. Electronic address: tatsuya.hayashi@mcn.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D003029:Coagulants / Q000737:chemistry*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011486:Protein C / Q000037:antagonists & inhibitors*; D018046:Protein C Inhibitor / Q000097:blood* / Q000737:chemistry; D012313:RNA / Q000032:analysis; D018180:Thrombomodulin / Q000737:chemistry; D019851:Thrombophilia / Q000097:blood*; D013997:Time Factors
chemical_list: D003029:Coagulants; D011486:Protein C; D018046:Protein C Inhibitor; C534934:SERPINA5 protein, human; C513537:SERPINA5 protein, mouse; D018180:Thrombomodulin; D012313:RNA
keywords: Neoplasm metastasis; Protein C; Protein C inhibitor; Serine protease inhibitors; Thrombomodulin