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Tissue Factor-Factor VIIa Complex Induces Epithelial Ovarian Cancer Cell Invasion and Metastasis Through a Monocytes-Dependent Mechanism
  1. Zhengwen Ma, PhD*,
  2. Ting Zhang, MD, PhD,
  3. Ruili Wang, MD,
  4. Zhongping Cheng, MD,
  5. Hong Xu, MD, PhD§,
  6. Weiping Li, MD, PhD§,
  7. Ying Wang, PhD and
  8. Xipeng Wang, MD, PhD
  1. * Department of Neurobiology, Shanghai JiaoTong University School of Medicine;
  2. Department of Gynecology, Shanghai First Maternity and Infant Hospital affiliated to Tongji University School of Medicine;
  3. Department of Obstetrics & Gynecology, Shanghai Yangpu Central Hospital; and
  4. § Department of Obstetrics & Gynecology, Renji Hospital, and
  5. Department of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  1. Address correspondence and reprint requests to Xipeng Wang, MD, PhD, Department of Gynecology, Shanghai First Maternity and Infant Hospital affiliated to Tongji University, Shanghai, 200040, China. E-mail: xipengwang{at}hotmail.com.

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.

Method: 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.

  • Epithelial ovarian cancer
  • Monocytes
  • Tissue factor-factor VII
  • Metastasis

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Footnotes

  • The authors declare no financial or commercial conflict of interest.

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