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).
J Natl Cancer Inst. 2014 Jun 19;106(7). doi: 10.1093/jnci/dju147. Print 2014 Jul.
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.
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.
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).
TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.
肿瘤相关性白细胞增多症（TRL）偶尔见于非血液系统恶性肿瘤患者。我们研究了 TRL 的临床意义以及 TRL 阳性宫颈癌的个体化治疗，并探讨了其潜在的生物学机制。
分析了 258 例接受根治性放疗的宫颈癌患者的临床数据，以研究 TRL 与治疗结果之间的关系。我们使用临床样本、宫颈癌细胞系和宫颈癌小鼠模型来研究宫颈癌中 TRL 的发生机制，重点关注肿瘤来源的粒细胞集落刺激因子（G-CSF）和髓源抑制细胞（MDSC）的作用。所有统计检验均为双侧检验。
TRL 与年龄较小（Wilcoxon 秩和检验，P =.03）、肿瘤较大（Wilcoxon 秩和检验，P =.006）、临床分期较晚（χ²检验，P =.01）和总生存时间较短（Cox 比例风险模型和 Wald 检验，P <.001）显著相关。在宫颈癌患者中，TRL 与肿瘤 G-CSF 表达上调（χ²检验，P <.001）、血清 G-CSF 水平升高（Student t 检验，P =.03）、脾脏增大（Student t 检验，P =.045）和血液中 MDSC 频率升高（Student t 检验，P <.001）相关，与 TRL 阴性患者相比。体外和体内实验表明，肿瘤源性 G-CSF 参与了 TRL 发生的潜在因果机制，而肿瘤源性 G-CSF 诱导的 MDSC 是 TRL 阳性宫颈癌快速进展和放疗抵抗的原因。抗 Gr-1 中和抗体的给药或脾切除术（每组 6 只）耗竭 MDSC 抑制了 TRL 阳性宫颈癌异种移植瘤的生长并增强了放疗敏感性（Wilcoxon 秩和检验，P =.008 和 P =.02）。
TRL 与宫颈癌患者对放疗的抵抗有关，针对 MDSC 的治疗可能对这些患者具有治疗潜力。
