title: The inhibition of pancreatic cancer invasion-metastasis cascade in both cellular signal and blood coagulation cascade of tissue factor by its neutralisation antibody.
abstract: Tissue factor (TF), the initiating cell surface receptor for the blood coagulation cascade, plays an important role in malignant transformation of the pancreas, although the precise mechanism remains unresolved. Here, we report that the TF - factor VIIa complex in human pancreatic cancer cells produced a significant amount of MMP-9 and promoted invasion ability in vitro and invasion and metastasis in vivo. For treatment, we successfully developed an anti-human TF monoclonal antibody that inhibits both cellular signalling and blood coagulation cascade via TF. Invasive capability and MMP-9 expression were significantly reduced by the antibody. The antibody inhibited not only tumour invasion in the orthotopic model, but also haematogenous metastasis in the portal-injection liver metastasis model. In conclusion, the TF-VIIa complex plays an important role in invasion-metastasis by enhancing tumour cell infiltration ability and forming microthrombi. The newly established anti-human TF neutralisation antibody may be useful for the treatment of pancreatic and other invasive cancers.
authors.affiliation: Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, and Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Kuroda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.forename: Amane
authors.initials: A
authors.lastname: Takahashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001777:Blood Coagulation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015942:Factor VIIa / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000502:physiology; D013925:Thromboplastin / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D009363:Neoplasm Proteins; D013925:Thromboplastin; D015942:Factor VIIa