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

被引：89

作者：

Mabuchi, Seiji ^{[1
]}

Matsumoto, Yuri ^{[1
]}

Kawano, Mahiru ^{[1
]}

Minami, Kazumasa ^{[2
]}

Seo, Yuji ^{[3
]}

Sasano, Tomoyuki ^{[1
]}

Takahashi, Ryoko ^{[1
]}

Kuroda, Hiromasa ^{[1
]}

Hisamatsu, Takeshi ^{[1
,4
]}

Kakigano, Aiko ^{[1
]}

Hayashi, Masami ^{[6
]}

Sawada, Kenjiro ^{[1
]}

Hamasaki, Toshimitsu

Morii, Eiichi ^{[5
]}

Kurachi, Hirohisa ^{[7
]}

Matsuura, Nariaki ^{[2
]}

Kimura, Tadashi ^{[1
]}

机构：

[1] Osaka Univ, Grad Sch Med, Dept Obstet & Gynecol, Suita, Osaka 5650871, Japan

[2] Osaka Univ, Grad Sch Med, Dept Mol Pathol, Suita, Osaka 5650871, Japan

[3] Osaka Univ, Grad Sch Med, Dept Radiat Oncol, Suita, Osaka 5650871, Japan

[4] Osaka Univ, Grad Sch Med, Dept Biomed Stat, Suita, Osaka 5650871, Japan

[5] Osaka Univ, Grad Sch Med, Dept Pathol, Suita, Osaka 5650871, Japan

[6] Osaka Med Coll, Dept Obstet & Gynecol, Osaka, Japan

[7] Yamagata Univ, Grad Sch Med, Dept Obstet & Gynecol, Yamagata 990, Japan

来源：

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2014年 / 106卷 / 07期

关键词：

SUPPRESSOR-CELLS; MYELOID CELLS; INHIBITION; CARCINOMA; INDICATOR; IMPROVES;

D O I：

10.1093/jnci/dju147

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (chi(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 (chi(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.

引用

页数：11