Myeloid-derived suppressor cells promote epithelial ovarian cancer cell stemness by inducing the CSF2/p-STAT3 signalling pathway.
髓源性抑制细胞通过诱导 CSF2/p-STAT3 信号通路促进上皮性卵巢癌细胞干性。
- 作者列表："Li X","Wang J","Wu W","Gao H","Liu N","Zhan G","Li L","Han L","Guo X
:Myeloid-derived suppressor cells (MDSCs) are known to contribute to tumour immune escape, studies have verified that MDSCs can induce cancer stem cells (CSCs) and promote tumour immune evasion in breast cancers, cervical cancers and glioblastoma. However, the potential function of MDSCs in regulating CSCs in epithelial ovarian cancer (EOC) progression is unknown. Our results indicated that compared to nonmalignant ovarian patients, EOC patients showed a significantly increased proportion of MDSCs in the peripheral blood. In addition, MDSCs dramatically promoted tumour sphere formation, cell colony formation and CSC accumulation, and MDSCs enhanced the expression of the stemness biomarkers NANOG and c-MYC in EOC cells during co-culture. Moreover, the mechanisms by which MDSCs enhance EOC stemness were further explored, and 586 differentially expressed genes were found in EOC cells co-cultured with or without MDSCs; during co-culture, the expression level of colony stimulating factor 2 (CSF2) was significantly increased in EOC cells co-cultured with MDSCs. Furthermore, the depletion of CSF2 in EOC cells was successfully performed, the promotive effects of MDSCs on EOC cell stemness could be markedly reversed by downregulating CSF2 expression, p-STAT3 signalling pathway molecules were also altered, and the p-STAT3 inhibitor could markedly reverse the promotive effects of MDSCs on EOC cell stemness. In addition, the CSF2 expression level was correlated with EOC clinical staging. Therefore, MDSCs enhance the stemness of epithelial ovarian cancer cells by inducing the CSF2/p-STAT3 signalling pathway. Targeting MDSCs or CSF2 may be a reasonable strategy for enhancing the efficacy of conventional treatments.
: 已知髓源性抑制细胞 (MDSCs) 有助于肿瘤免疫逃逸，研究证实 MDSCs 可以诱导癌症干细胞 (CSCs) 并促进乳腺癌的肿瘤免疫逃避,宫颈癌和胶质母细胞瘤。然而，MDSCs 在上皮性卵巢癌 (EOC) 进展中调节 CSCs 的潜在功能尚不清楚。我们的结果表明，与非恶性卵巢患者相比，EOC 患者外周血中 MDSCs 的比例显著增加。此外，MDSCs 显著促进肿瘤球形成、细胞集落形成和 CSC 积累，MDSCs 在共培养过程中增强了 EOC 细胞中干性生物标志物 NANOG 和 c-MYC 的表达。此外，进一步探讨了 MDSCs 增强 EOC 干性的机制，在与或不与 MDSCs 共培养的 EOC 细胞中发现了 586 个差异表达基因; 在共培养过程中,在与 MDSCs 共培养的 EOC 细胞中，集落刺激因子 2 (CSF2) 的表达水平显著升高。此外，成功地在 EOC 细胞中去除 CSF2，MDSCs 对 EOC 细胞干性的促进作用可通过下调 CSF2 的表达而显著逆转，p-STAT3 信号通路分子也发生了改变。p-STAT3 抑制剂可明显逆转 MDSCs 对 EOC 细胞干性的促进作用。此外，CSF2 表达水平与 EOC 临床分期相关。因此，MDSCs 通过诱导 CSF2/p-STAT3 信号通路增强上皮性卵巢癌细胞的干性。靶向 MDSCs 或 CSF2 可能是增强常规治疗疗效的合理策略。
METHODS:STUDY OBJECTIVE:To evaluate the differences in perioperative outcomes and immediate complication rates between laparoscopic myomectomy for submucous myomas and laparoscopic myomectomy for myomas in other locations. DESIGN:Retrospective cohort study. SETTING:University-affiliated hospital in London. PATIENTS:A total of 350 patients with symptomatic uterine myomas underwent laparoscopic myomectomy. Thirty-three of these were performed for submucous myomas (group 1), and 317 were for myomas in other uterine locations (group 2). INTERVENTIONS:Analysis of prospectively collected data on patient demographics, myoma characteristics, perioperative outcomes, and immediate complications. MEASUREMENTS AND MAIN RESULTS:Patient demographics, including age, body mass index, and parity, were similar in the 2 groups. No significant differences in myoma characteristics were seen between groups 1 and 2, including the mean dimension of largest myoma (7.1 vs 7.8 cm, respectively; p = .35), mean number of myomas removed (3.8 vs 4.1; p = .665), and mean mass of myomas removed (142.0 g vs 227.3 g; p = .186). There were also no significant between-group differences in any perioperative outcomes, including mean blood loss (226.8 mL vs 266.4 mL; p = .373), duration of surgery (103 minutes vs 113 minutes; p = .264), and duration of hospital stay (1.4 days vs 1.7 days; p = .057). No complications arose from laparoscopic resection of submucous myomas. CONCLUSION:Laparoscopic myomectomy for submucous myomas has similar perioperative outcomes and immediate complications as laparoscopic myomectomy for other myomas and can be considered for large or type 2 submucous myomas.
METHODS:INTRODUCTION:Laparoscopic myomectomy can be difficult when fibroids are large and numerous. This may result in extensive intraoperative bleeding and the need for a conversion to a laparotomy. Medical pretreatment prior to surgery might reduce these risks by decreasing fibroid size and vascularization of the fibroid. We compared pretreatment with ulipristal acetate (UPA) vs gonadotropin-releasing hormone agonists (GnRHa) prior to laparoscopic myomectomy on several intra- and postoperative outcomes. MATERIAL AND METHODS:We performed a non-inferiority double-blind randomized controlled trial in nine hospitals in the Netherlands. Women were randomized between daily oral UPA for 12 weeks and single placebo injection or single intramuscular injection with leuprolide acetate and daily placebo tablets for 12 weeks. The primary outcome was intraoperative blood loss. Secondary outcomes were reduction of fibroid volume, suturing time, total surgery time and surgical ease. RESULTS:Thirty women received UPA and 25 women leuprolide acetate. Non-inferiority of UPA regarding intraoperative blood loss was not demonstrated. When pretreated with UPA, median intraoperative blood loss was statistically significantly higher (525 mL [348-1025] vs 280 mL[100-500]; P = 0.011) and suturing time of the first fibroid was statistically significantly longer (40 minutes [28-48] vs 22 minutes [14-33]; P = 0.003) compared with GnRHa. Pretreatment with UPA showed smaller reduction in fibroid volume preoperatively compared with GnRHa (-7.2% [-35.5 to 54.1] vs -38.4% [-71.5 to -19.3]; P = 0.001). Laparoscopic myomectomies in women pretreated with UPA were subjectively judged more difficult than in women pretreated with GnRHa. CONCLUSIONS:Non-inferiority of UPA in terms of intraoperative blood loss could not be established, possibly due to the preliminary termination of the study. Pretreatment with GnRHa was more favorable than UPA in terms of fibroid volume reduction, intraoperative blood loss, hemoglobin drop directly postoperatively, suturing time of the first fibroid and several subjective surgical ease parameters.
METHODS:AIMS:Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS:We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION:Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.