Journal
INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
Volume 21, Issue 4, Pages 616-624Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/IGC.0b013e3182150e98
Keywords
Epithelial ovarian cancer; Monocytes; Tissue factor-factor VII; Metastasis
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Funding
- National Science Foundation of China [30600672]
- Qimingxing Project [06QH14010]
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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 alpha 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-1 alpha, HIF-1 beta, 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.
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