Uterine Cervical Cancer Displaying Tumor-Related Leukocytosis: A Distinct Clinical Entity With Radioresistant Feature

Mabuchi, Seiji; Matsumoto, Yoshihisa; Kawano, Mahiru; Minami, Kazumasa; Seo, Yuji; Sasano, Tomoyuki; Takahashi, Ryoko; Kuroda, Hiromasa; Hisamatsu, Takeshi; Kakigano, Aiko; Hayashi, Masami; Sawada, Kenjiro; Hamasaki, Toshimitsu; Morii, Eiichi; Kurachi, Hirohisa; Matsuura, Nariaki; Kimura, Tadashi

doi:10.1093/jnci/dju147

Cited by 112 publications

(156 citation statements)

References 19 publications

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“…G-CSF expression has been detected in the tumors of many solid malignancies, including breast cancer (46)(47)(48)(49), and tumors that express G-CSF have been found to be more aggressive and associated with increased likelihood of recurrence (46). G-CSF can induce T-cell tolerance and has been shown to drive MDSC development from human hematopoietic stem cells cultured in vitro (31,49).…”

Section: Discussionmentioning

confidence: 99%

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

Chafe¹,

Lou²,

Sceneay

et al. 2015

Cancer Research

117

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The mobilization of bone marrow-derived cells (BMDC) to distant tissues before the arrival of disseminated tumor cells has been shown preclinically to facilitate metastasis through the establishment of metastatic niches. Primary tumor hypoxia has been demonstrated to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX, CA9) expression is highly upregulated in hypoxic breast cancer cells through the action of hypoxia-inducible factor-1 (HIF1). Preclinical evidence has demonstrated that CAIX is required for breast tumor growth and metastasis; however, the mechanism by which CAIX exerts its prometastatic function is not well understood. Here, we show that CAIX is indispensable for the production of granulocyte colony-stimulating factor (G-CSF) by hypoxic breast cancer cells and tumors in an orthotopic model. Furthermore, we demonstrate that tumor-expressed CAIX is required for the G-CSF-driven mobilization of granulocytic myeloid-derived suppressor cells (MDSC) to the breast cancer lung metastatic niche. We also determined that CAIX expression is required for the activation of NF-kB in hypoxic breast cancer cells and constitutive activation of the NF-kB pathway in CAIX-depleted cells restored G-CSF secretion. Together, these findings identify a novel hypoxia-induced CAIX-NF-kB-G-CSF cellular signaling axis culminating in the mobilization of granulocytic MDSCs to the breast cancer lung metastatic niche. Cancer Res; 75(6); 996-1008.Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

Chafe¹,

Lou²,

Sceneay

et al. 2015

Cancer Research

117

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“…G-CSF is produced by a tumor and in turn induces the production of myeloid-derived suppressor cells (MDSCs). These MDSCs cause rapid progression of cervical cancer and leukocytosis and radioresistance [18]. Mabuchi et al depleted MDSCs, which succeeded in inhibiting the progression of cervical cancer and leukocytosis and enhancing radiosensitivity [18].…”

Section: Discussionmentioning

confidence: 99%

“…These MDSCs cause rapid progression of cervical cancer and leukocytosis and radioresistance [18]. Mabuchi et al depleted MDSCs, which succeeded in inhibiting the progression of cervical cancer and leukocytosis and enhancing radiosensitivity [18]. MDSCs have been found in bone marrow, blood, and the spleen of individuals with tumors.…”

Section: Discussionmentioning

confidence: 99%

The pretreatment neutrophil-to-lymphocyte ratio predicts therapeutic response to radiation therapy and concurrent chemoradiation therapy in uterine cervical cancer

et al. 2015

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Objective: The aim of this study was to investigate the prognostic role of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a predictive marker prior to treatment of cervical cancer with radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT).Methods: Fifty-six patients with squamous cell carcinoma (SCC) of the uterine cervix who underwent RT or CCRT from 2005 to 2013 at this Hospital were retrospectively identified using electronic databases.Patients were divided into a high NLR group (≥ 2.5) and a low NLR group (< 2.5). The efficacy of RT and CCRT in the two groups was compared.Result: Of the 56 patients, 35 were in the high NLR group and 21 were in the low NLR group. In comparison to a high NLR, a low NLR was significantly associated with a complete response (P < 0.001).When cancer was divided into stages I/II and III/IV, patients with a low NLR had a significantly better therapeutic outcome than those with a high NLR (P < 0.05). Multivariate analysis showed that only the NLR was a significant prognostic factor for progression-free survival (PFS). Patients with a high NLR had a significantly shorter PFS and overall survival than those with a low NLR.Conclusion: Results showed that a low NLR before treatment can predict a good response to RT or CCRT by all stages of uterine cervical cancer. The NLR may be a promising parameter on which to base the choice of a therapeutic strategy to treat SCC of the uterine cervix.

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“…Indeed, it has been recently demonstrated that MDSCs can suppress T cells in the spleen promoting tumor immunosuppression (22). Accordingly, splenectomy in mice can change the amount of tumorinfiltrating MDSCs, promoting tumor regression in murine models of cancer (42). Therefore, MDSCs in cancer patients may affect tumorigenesis by acting in multiple sites, not only in the tumors.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting Tumor-Infiltrating Myeloid-Derived Suppressor Cells for Cancer Therapy

Mitri

Alimonti

2015

Clinical Cancer Research

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Tumor-infiltrating myeloid-derived suppressor cells (MDSC) are a heterogeneous and immunosuppressive cell subset that blocks the proliferation and the activity of both T and natural killer (NK) cells and promotes tumor vasculogenesis and progression. Recent evidences demonstrate that the recruitment of MDSCs in tumors also blocks senescence induced by chemotherapy promoting chemoresistance. Hence, the need of novel therapeutic approaches that can efficiently target MDSC recruitment and function in cancer. Among them, novel combinatorial treatments of chemotherapy and immunotherapy or treatments that induce depletion of MDSCs in peripheral sites should be taken in consideration.

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Uterine Cervical Cancer Displaying Tumor-Related Leukocytosis: A Distinct Clinical Entity With Radioresistant Feature

Abstract: TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.

Cited by 112 publications

References 19 publications

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

The pretreatment neutrophil-to-lymphocyte ratio predicts therapeutic response to radiation therapy and concurrent chemoradiation therapy in uterine cervical cancer

Molecular Pathways: Targeting Tumor-Infiltrating Myeloid-Derived Suppressor Cells for Cancer Therapy

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