Abstract
Granulocyte-colony stimulating factor (G-CSF) producing malignant tumor has been reported to occur in various organs, and has been associated with poor clinical outcome. The aim of this study is to investigate the significance of tumor G-CSF expression in the chemosensitivity of uterine cervical cancer. The clinical data of recurrent or advanced cervical cancer patients who were treated with platinum-based chemotherapy were analyzed. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms responsible for the development of chemoresistance in G-CSF-producing cervical cancer, focusing on myeloid-derived suppressor cells (MDSC). As a result, the tumor G-CSF expression was significantly associated with increased MDSC frequencies and compromised survival. In vitro and in vivo experiments demonstrated that the increased MDSC induced by tumor-derived G-CSF is involved in the development of chemoresistance. The depletion of MDSC via splenectomy or the administration of anti-Gr-1 antibody sensitized G-CSF-producing cervical cancer to cisplatin. In conclusion, tumor G-CSF expression is an indicator of an extremely poor prognosis in cervical cancer patients that are treated with chemotherapy. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy as a treatment for G-CSF-producing cervical cancer.
Highlights
Cervical cancer, which has an annual global incidence of 530,000 new cases, is the second most common type of cancer affecting women worldwide[1]
To understand the clinical significance of granulocyte-colony stimulating factor (G-CSF) expression in cervical cancer patients who are treated with chemotherapy, we evaluated the associations between G-CSF immunoreactivity and the response rate or survival after chemotherapy
As it has been reported that G-CSF inhibits the spontaneous neutrophil apoptosis through the induction of Janus kinase 2 (JAK2)- Signal transducer and activator of transcription 3 (Stat3) pathway[13], we investigated the effect of G-CSF on Stat[3] pathway activation in myeloid-derived suppressor cells (MDSC) and the survival of MDSC
Summary
Cervical cancer, which has an annual global incidence of 530,000 new cases, is the second most common type of cancer affecting women worldwide[1]. TRL can be caused by the upregulated expression of hematological growth factors, including granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha[8] Among these cytokines, G-CSF produced by tumor cells has recently been shown to stimulate tumor progression by facilitating tumor angiogenesis, promoting metastasis, and inducing immune suppression through the increased mobilization of myeloid-derived suppressor cells (MDSC) from the bone marrow[9,10]. We have recently reported that TRL-positive cervical cancer expresses G-CSF, is rapidly progressive, highly likely to develop resistance to radiotherapy, and is associated with recurrent or persistent disease[11]. We examined the prognostic significance of tumor G-CSF expression in patients with recurrent or metastatic cervical cancer that had been treated with platinum-based chemotherapy. After investigating the underlying causative mechanism in in vitro and in vivo experimental models we proposed novel treatment strategies for overcoming the chemoresistance of G-CSF-producing cervical cancer
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