Abstract
Abstract Objectives: Granulocyte-colony stimulating factor (G-CSF) is known to induce the myeloid-derived suppressor cells (MDSCs) to stimulate the progression of uterine cervical cancer. The aim of this study was to investigate the role of G-CSF and the MDSCs in the invasion and the metastasis of uterine cervical cancer. Methods: We first established cervical cancer cell lines stably transfected with G-CSF expression vector (ME180-GCSF) or control vector (ME180-control). Then, using mice subcutaneously inoculated with ME180-control or ME180-GCSF cells, the effect of G-CSF on the induction of MDSCs (CD11b+Gr1+ cells) and the metastatic activity of cervical cancer cells. The association of MDSCs infiltration and the clinical outcome was also assessed immunohistochemically using tumor samples obtained from cervical cancer patients. Finally, using MDSCs isolated from the spleen of the ME180-GCSF-bearing mice, we investigated whether the MDSCs facilitate the invasive or metastatic activities of uterine cervical cancer in vitro and in vivo. Results: 1) ME180-GCSF-derived tumors contain greater number of MDSC, more frequently develop lymphovascular space invasion, and developed greater number of metastatic tumors than ME180-control-tumors. 2) Immunohistochemical analyses using human samples revealed that increased MDSC counts were significantly associated with deep stromal invasion and lymphovascular space invasion. 3) MDSCs were recruited into cervical cancer via CXCL12-CXCR4 axis. 4) Coincubation of MDSCs with ME180 cells increased the invasive activity of ME180 cells. 5) The depletion of MDSCs significantly decreased the invasive and metastatic activities of ME180 cells. Conclusions: Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis by recruiting MDSCs. MDSCs and CXCL12-CXCR4 axis might be promising therapeutic targets in patients with uterine cervical cancer. Citation Format: Tomoyuki Sasano, Seiji Mabuchi, Ryoko Takahashi, Hiromasa Kuroda, Kenjiro Sawada, Tadashi Kimura. Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis of uterine cervical cancer by recruiting myeloid-derived suppressor cells (MDSCs) via CXCL12-CXCR4 axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 438. doi:10.1158/1538-7445.AM2015-438
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