The aim of this study was to investigate the metastatic potential of uterine cervical and endometrial cancer displaying tumor-related leukocytosis (TRL). Clinical data on uterine cervical ( = 732) and endometrial cancer ( = 900) were collected, and the metastatic potential of TRL-positive cancer was evaluated in univariate and multivariate analyses. Tumor and blood samples obtained from patients with cervical cancer, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms underlying the highly metastatic nature of TRL-positive cancer, focusing on tumor-derived G-CSF and the myeloid-derived suppressor cell (MDSC)-mediated premetastatic niche. Pretreatment TRL was significantly associated with visceral organ metastasis in patients with uterine cervical or endometrial cancer. The patients with TRL-positive cervical cancer displayed upregulated tumor G-CSF expression, elevated G-CSF levels, and increased MDSC frequencies in the peripheral blood compared with the TRL-negative patients. and investigations revealed that MDSCs produced in response to tumor-derived G-CSF are involved in premetastatic niche formation, which promotes visceral organ metastasis of TRL-positive cancer. The depletion of MDSCs attenuated this premetastatic niche formation and effectively inhibited the visceral organ metastasis of TRL-positive cancer. Uterine cervical/endometrial cancer displaying TRL is a distinct clinical entity with high metastatic potential. Tumor-derived G-CSF and the MDSC-mediated premetastatic niche are responsible for the highly metastatic nature of this type of cancer. MDSC-targeting therapy might represent a potential strategy for combating metastasis derived from TRL-positive uterine cancer. .

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The accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) can be influenced by the increased glycolytic activity of inflammatory lesions. Here, using clinical data obtained from gynecological cancer patients, tumor samples and animal models, we investigate the impact of pretreatment tumor-related leukocytosis (TRL) on the diagnostic performance of 18F-FDG-PET/CT in detecting pelvic and paraaortic lymph node metastasis. We demonstrate that pretreatment TRL misleads 18F-FDG-PET/CT during lymph node staging in gynecological malignancies. In the mechanistic investigations, we show that the false-positive 18F-FDG-PET/CT result for detecting nodal metastasis can be reproduced in animal models of TRL-positive cancer bearing G-CSF expressing cervical cancer cells. We also show that increased 18F-FDG uptake in nonmetastatic nodes can be explained by the MDSC-mediated premetastatic niche formation in which proinflammatory factors, such as S100A8 or S100A9, are abundantly expressed. Together, our results suggest that the MDSC-mediated premetastatic niche created in the lymph node of TRL-positive patients misleads 18F-FDG-PET/CT for detecting nodal metastasis. 1 1234567890():,; ≥9000 6 (35.3) 11 (64.7) 7 (41.2) 10 (58.8) 5 (41.7) 7 (58.3) Statistical significance was assessed using two-sided Fisher's exact test. FDG fluorodeoxyglucose, PET positron emission tomography, CT computed tomography, WBC white blood cell.

Myeloid-derived suppressor cells (MDSCs) enhance tumor progression by suppressing tumor-specific T cell responses, stimulating tumor angiogenesis, or promoting tumor cell metastasis. However, the biology of MDSCs have not been fully investigated. In the current study, we investigated the role of MDSCs in inducing cancer stem-like cells and explored a clinically feasible approach for targeting MDSCs-mediated cancer stem-like cells induction. In vitro and in vivo experiments revealed that MDSCs induced by tumor-derived G-CSF enhanced the stemness of cervical cancer cells by producing Prostaglandin E2 (PGE2). We also demonstrated that anti-Gr-1 neutralizing antibody or celecoxib inhibited the induction of cancer stem-like cells and enhanced the efficacy of cisplatin in cervical cancer. In clinical samples, MDSCs, PGE2, and CSCs had positive correlations. In conclusion, G-CSF-induced MDSCs enhance the stemness of uterine cervical cancer cells by producing PGE2. Targeting MDSCs or PGE2 might be a reasonable strategy for enhancing the efficacies of treatments.

ObjectiveTo compare the clinical utilities of the platelet count and platelet-lymphocyte ratio (PLR) for predicting survival in patients with cervical cancer.ResultsMultivariate analyses demonstrated that thrombocytosis and elevated PLR were found to be independent prognostic factors for progression-free survival (PFS, P = 0.0077, P = 0.044) and overall survival (OS, P = 0.025, P = 0.019) in separate Multivariate analyses. In the ROC analysis, the platelet count showed a significantly greater area under the ROC curve (AUC) value than that of PLR for predicting patient recurrence (0.5941 versus 0.5331, p = 0.018) and survival (0.6139 versus 0.5468, p = 0.029). In patients without thrombocytosis, elevated PLR correlated with shorter survival (PFS, P = 0.041; OS, P = 0.017). In contrast, PLR in patients with thrombocytosis did not provide prognostic information. We divided patients into 3 prognostic groups using platelet counts and PLR: high-risk (thrombocytosis with any PLR); intermediate-risk (elevated PLR without thrombocytosis); low-risk (none of the above), which allowed for individualized and accurate survival estimates.Materials and MethodsThe baseline characteristics and clinical outcomes of cervical cancer patients were identified. Patients were grouped according to their pretreatment platelet counts or PLR, and clinicopathological characteristics and patient survival were then compared between these groups. The clinical utilities of the platelet count and PLR were compared using a time-dependent receiver operating characteristic (ROC) analysis.ConclusionsPretreatment thrombocytosis and elevated PLR were identified as independent predictors in cervical cancer patients. Platelet counts were superior to PLR for predicting the prognosis of uterine cervical cancer patients. Our prognostic model consisting of platelet counts and PLR offers individualized survival estimates.