title: Tissue factor-factor VIIa complex induces epithelial ovarian cancer cell invasion and metastasis through a monocytes-dependent mechanism.
abstract: OBJECTIVE
  Tumor-associated macrophage infiltration and up-regulation of tissue factor-factor VII (TF-FVIIa) complex have been observed in the peritoneum and stroma of epithelial ovarian cancer (EOC). However, it is not clear how tumor-associated macrophage and TF-FVIIa complex promotes EOC invasion. In the present study, we aimed to determine the mechanism by which interaction of TF-FVIIa and monocytes (MOs) promotes EOC metastasis.
  
  
  METHODS
  Matrigel invasion assay was used to analyze the potential of EOC metastasis. Enzyme-linked immunosorbent assay and real-time polymerase chain reaction were used to detect expressions of cytokines and chemokines. Fluorescence-activated cell sorting was used to count the percentage of CD14, CD68, and CD163 of MOs.
  
  
  RESULTS
  We found that the TF-FVIIa complex caused dynamic changes in MOs cytokine and chemokine expression. CD14 and CD163 were also upregulated on MOs by TF-FVIIa. Epithelial ovarian cancer cells were cocultured with TF-FVIIa-stimulated MOs, demonstrating increased invasion potential. Interleukin 8 (IL-8) was proposed as the major chemoattractant mediating EOC invasion based on MOs messenger RNA and protein expression profiles. Anti-IL-8 monoclonal neutralizing antibody attenuated EOC cell invasion in a concentration-dependent manner, and tumor necrosis factor α from TF-FVIIa-stimulated MOs was observed to amplify IL-8 production. The following transcription factors in MOs were activated by TF-FVIIa and inhibited by the tissue factor pathway inhibitor: oncogenes HIF-1α, HIF-1β, Oct I, Oct II, and Egr-1; inflammatory mediators c-Fos and c-Rel; and STAT family members STAT5A and STAT5B.
  
  
  CONCLUSIONS
  Our study suggested that the interaction between the TF-FVIIa complex might play a role in mediating EOC invasion and metastasis depending on MOs mechanism.
authors.affiliation: Department of Neurobiology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Ma
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Ruili
authors.initials: R
authors.lastname: Wang
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Cheng
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Weiping
authors.initials: W
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Xipeng
authors.initials: X
authors.lastname: Wang
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015942:Factor VIIa / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013925:Thromboplastin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; D013925:Thromboplastin; D015942:Factor VIIa