Purpose: The aim of this study was to investigate the metastatic potential of uterine cervical and endometrial cancer displaying tumor-related leukocytosis (TRL). Experimental Design: Clinical data on uterine cervical (N=732) and endometrial cancer (N=900) were collected, and the metastatic potential of TRL-positive cancer was evaluated in univariate and multivariate analyses. Tumor and blood samples obtained from cervical cancer patients, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms underlying the highly metastatic nature of TRL-positive cancer, focusing on tumor-derived granulocyte-colony stimulating factor (G-CSF) and the myeloid-derived suppressor cells (MDSC)-mediated premetastatic niche. Results: Pretreatment TRL was significantly associated with visceral organ metastasis in patients with uterine cervical or endometrial cancer. The TRL-positive cervical cancer patients displayed upregulated tumor G-CSF expression, elevated G-CSF levels, and increased MDSC frequencies in the peripheral blood compared with the TRL-negative patients. In vitro and in vivo investigations revealed that MDSC 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 MDSC attenuated this premetastatic niche formation and effectively inhibited the visceral organ metastasis of TRL-positive cancer. Conclusions: 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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