Papadaki Maria A, Monastirioti Alexia, Apostolopoulou Christina A, Aggouraki Despoina, Papadaki Chara, Michaelidou Kleita, Vassilakopoulou Maria, Alexakou Katerina, Mavroudis Dimitrios, Agelaki Sofia
Laboratory of Translational Oncology, School of Medicine, University of Crete, 71110 Heraklion, Greece.
Department of Medical Oncology, University General Hospital of Heraklion, 71110 Heraklion, Greece.
Cancers (Basel). 2022 Feb 18;14(4):1053. doi: 10.3390/cancers14041053.
TLR4 and pSTAT3 are key players in cancer inflammation and immune evasion; however, their role in the peripheral blood (PB) is largely unexplored. Herein we evaluated their expression in the circulating tumor cells (CTCs) and peripheral-blood mononuclear cells (PBMCs) of patients with early ( = 99) and metastatic ( = 100) breast cancer (BC). PB samples obtained prior to adjuvant and first-line therapy, were immunofluorescently stained for Cytokeratins/TLR4/pSTAT3/DAPI and analyzed via Ariol microscopy. TLR4+ CTCs were detected in 50% and 68% of early and metastatic CTC-positive patients, respectively, and pSTAT3+ CTCs in 83% and 68%, respectively. In metastatic patients, CTC detection was associated with a high risk of death (HR: 1.764, = 0.038), while TLR4+ CTCs correlated with a high risk of disease progression (HR: 1.964, = 0.030). Regarding PBMCs, TLR4 expression prevailed in metastatic disease ( = 0.029), while pSTAT3 expression was more frequent in early disease ( = 0.014). In early BC, TLR4 expression on PBMCs independently predicted for high risk of relapse (HR: 3.549; = 0.009), whereas in metastatic BC, TLR4+/pSTAT3- PBMCs independently predicted for high risk of death (HR: 2.925; = 0.012). These results suggest that TLR4/pSTAT3 signaling on tumor- and immune-cell compartments in the PB could play a role in BC progression, and may hold independent prognostic implications for BC patients.
Toll样受体4（TLR4）和磷酸化信号转导子和转录激活子3（pSTAT3）是癌症炎症和免疫逃逸的关键因子；然而，它们在外周血（PB）中的作用在很大程度上尚未得到探索。在此，我们评估了它们在早期（n = 99）和转移性（n = 100）乳腺癌（BC）患者的循环肿瘤细胞（CTC）和外周血单个核细胞（PBMC）中的表达。在辅助治疗和一线治疗前采集的PB样本，用细胞角蛋白/TLR4/pSTAT3/4',6-二脒基-2-苯基吲哚（DAPI）进行免疫荧光染色，并通过Ariol显微镜进行分析。在早期和转移性CTC阳性患者中，分别有50%和68%检测到TLR4+ CTC，分别有83%和68%检测到pSTAT3+ CTC。在转移性患者中，CTC检测与高死亡风险相关（风险比：1.764，P = 0.038），而TLR4+ CTC与高疾病进展风险相关（风险比：1.964，P = 0.030）。关于PBMC，TLR4表达在转移性疾病中占优势（P = 0.029），而pSTAT3表达在早期疾病中更常见（P = 0.014）。在早期BC中，PBMC上的TLR4表达独立预测高复发风险（风险比：3.549；P = 0.009），而在转移性BC中，TLR4+/pSTAT3- PBMC独立预测高死亡风险（风险比：2.925；P = 0.012）。这些结果表明，PB中肿瘤细胞和免疫细胞区室上的TLR4/pSTAT3信号传导可能在BC进展中起作用，并且可能对BC患者具有独立的预后意义。
