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Thrombin facilitates invasion of ovarian cancer along peritoneum by inducing monocyte differentiation toward tumor-associated macrophage-like cells

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Abstract

Peritoneal metastasis is a distinct pathologic characteristic of advanced epithelial ovarian cancer (EOC), which is the most deadly disease of the female reproductive tract. The inflammatory environment of the peritoneum in EOC contains abundant macrophages, activated thrombin, and thrombin-associated receptors. However, little is known about the mechanism by which the thrombin–macrophages interaction contributes to tumor invasion and metastasis. We investigated the phenotype and cytokine/chemokine expression of thrombin-treated peripheral blood monocytes (MOs)/macrophages, it was found that the phenotype of MOs was altered toward a TAM-like macrophage CD163highIL-10highCCL18highIL-8high after thrombin stimulation. By Matrigel invasion assay, the conditioned medium of thrombin-stimulated MOs accelerated remarkable invasion of ES-2, SKOV3, and HO-8910, which was similar to invasive cell numbers of ascites stimuli (P < 0.05) and higher than MOs medium alone (P < 0.05). IL-8 was proposed as the major chemoattractant mediating EOC invasion based on MOs mRNA and protein expression profiling. It was observed that anti IL-8 monoclonal neutralizing antibody attenuated EOC cell invasion in a concentration-dependent manner. Increased transcriptional activation of NF-κB p50/p65 was identified in thrombin-treated MOs. This study provided insight the role of thrombin in the regulation of EOC peritoneal invasion via “educating” MOs.

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Acknowledgments

We appreciate the assistance of Professor Peihua Lu, who kindly provided lab instruments to support this study. This study was supported by the grants from National Science Foundation of China (30600672) and Shanghai Qimingxing Star Project (06QH14010).

Conflict of interest statement

All authors are aware of and agree to the content of the paper and to being listed as an author on the paper. All authors declare that there is no conflict of interest including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding in this paper.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China

    Ting Zhang, Ruili Wang, Hong Xu, Xinjuan Jin, Weiping Li & Xipeng Wang

  2. Department of Neurobiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Zhengwen Ma

  3. Department of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200023, China

    Ying Wang & Shujun Wang

  4. Department of Obstetrics and Gynecology, Shanghai Yangpu Central Hospital, Shanghai, 200090, China

    Zhongping Cheng

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  1. Ting Zhang
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Correspondence to Weiping Li or Xipeng Wang.

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Zhang, T., Ma, Z., Wang, R. et al. Thrombin facilitates invasion of ovarian cancer along peritoneum by inducing monocyte differentiation toward tumor-associated macrophage-like cells. Cancer Immunol Immunother 59, 1097–1108 (2010). https://doi.org/10.1007/s00262-010-0836-y

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