title: Uterine cervical cancer displaying tumor-related leukocytosis: a distinct clinical entity with radioresistant feature.
abstract: BACKGROUND
  Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism.
  
  
  METHODS
  Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided.
  
  
  RESULTS
  TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (χ(2) test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ(2) test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively).
  
  
  CONCLUSIONS
  TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK). smabuchi@gyne.med.osaka-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Yuri
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Mahiru
authors.initials: M
authors.lastname: Kawano
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Minami
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Yuji
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sasano
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Kuroda
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hisamatsu
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Aiko
authors.initials: A
authors.lastname: Kakigano
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Masami
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Hamasaki
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK).
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects*; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D007964:Leukocytosis / Q000209:etiology*; D051379:Mice; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D017211:Treatment Failure; D002583:Uterine Cervical Neoplasms / Q000150:complications* / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D016179:Granulocyte Colony-Stimulating Factor