title: Extrahepatic synthesis of coagulation factor VII by colorectal cancer cells promotes tumor invasion and metastasis.
abstract: BACKGROUND
  Blood coagulation factor VII (FVII) is physiologically synthesized in the liver and released into the blood. Binding of FVII to tissue factor (TF) is related to the metastatic potential of tumor cells, also a significant risk factor in the development of hepatic metastasis in patients with colorectal cancer (CRC). It has been found that some cancer cells can produce FVII extrahepatically. However, little is known about FVII and CRC. We therefore hypothesized that CRC cells may synthese FVII, leading to tumor invasion and metastasis.
  
  
  METHODS
  We detected the expression of FVII protein in 55 CRC specimens by immunohistochemical staining. The FVII mRNA in 45 of 55 CRC cases, 6 colon cancer cell lines and one hepatoma cell line was measured by real-time reverse transcription-PCR (RT-PCR). Transwell invasion assays were performed to evaluate the changes of cell migration and invasion of LoVo cancer cells in vitro. We further observed the likely effectors regulated by the TF/FVIIa complex Western blotting assay.
  
  
  RESULTS
  Extrahepatic synthesis of FVII was detected in the cytoplasm of 32 (58.2%) CRC specimens by immunohistochemistry, but not in normal mucosa. Liver metastasis (P = 0.003) and TNM staging (P = 0.005) were significantly correlated with FVII antigen expression. The positive ratios in stages I, II, III and IV were 33.3%, 40.0%, 52.4% and 87.5%, respectively. The expression of FVII mRNA in CRC with hepatic metastasis was significantly higher than CRC without hepatic metastasis (5.33 ± 2.88 vs. 1.47 ± 0.51, P = 0.03). Ectopic FVIIa induced a slight increase (1.34-fold) in the number of migrating cells, which was inhibited by the specific TF antibody. The formation of TF/FVIIa complex resulted in a marked increase in the expression of matrix metalloproteinases (MMP)-2 (3.5-fold) and MMP-9 (4.7-fold) in a time-dependent and dose-dependent manner.
  
  
  CONCLUSIONS
  Extrahepatic synthesis of FVII by CRC cells may promote tumor invasion and metastasis. MMPs, as downstream effectors of TF/FVIIa signaling, facilitate the development of metastasis in colon cancer.
authors.affiliation: Department of General Surgery, Peking University First Hospital, Beijing 100034, China.
authors.forename: Jian-Qiang
authors.initials: JQ
authors.lastname: Tang
authors.forename: Qing
authors.initials: Q
authors.lastname: Fan
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Wu
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Jia
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yin-Mo
authors.initials: YM
authors.lastname: Yang
authors.forename: Yu-Cun
authors.initials: YC
authors.lastname: Liu
authors.forename: Yuan-Lian
authors.initials: YL
authors.lastname: Wan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005167:Factor VII / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000032:analysis; D013925:Thromboplastin / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D005167:Factor VII; D013925:Thromboplastin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9