Wu Chun-Te, Huang Yun-Ching, Chen Wen-Cheng, Chen Miao-Fen
Department of Urology, Chang Gung Memorial Hospital at KeeLung, Keelung 20401, Taiwan.
College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Cancers (Basel). 2019 Jul 16;11(7):992. doi: 10.3390/cancers11070992.
Local treatment is known to improve survival in men with locally advanced prostate cancer (LAPC), but the underlying mechanisms remain unclear. In the present study, we examined the role of tumor burden in tumor aggressiveness, as well as the pathway responsible for these changes. We used human and murine prostate cancer cell lines to examine the role of tumor burden in tumor aggressiveness, as well as its correlation with cancer stem cell (CSC) marker levels and IL-6 signaling. Furthermore, 167 prostate cancer biopsy specimens were analyzed in terms of correlations of IL-6 and CD44 levels with clinical patient characteristics. Data from preclinical models showed that larger tumor burden was associated with more aggressive tumor growth associated and increased CD44 expression. Using cellular experiments and orthotopic tumor models, we showed that CD44+ prostate cancer cells have CSC-like properties, enhanced epithelial-mesenchymal transition (EMT), and a more immunosuppressive microenvironment. There was a significant correlation between IL-6 and CD44 levels based on in vitro testing of clinical samples. Blockade of IL-6/STAT3 signaling attenuated the expression of CD44, CSC-like properties, and aggressive tumor behavior in vitro and in vivo. In conclusion, CD44 expression is significantly associated with tumor aggressiveness in prostate cancer and activation of IL-6 signaling leads to a suitable microenvironment for the induction of CD44 expression. Based on our study, reduced tumor burden was associated with attenuated IL-6 signaling and augmented tumor rejection in the microenvironment, which might mediate the benefit of clinical adoption with aggressive local therapy.
已知局部治疗可提高局部晚期前列腺癌（LAPC）男性患者的生存率，但其潜在机制仍不清楚。在本研究中，我们研究了肿瘤负荷在肿瘤侵袭性中的作用，以及导致这些变化的途径。我们使用人源和鼠源前列腺癌细胞系来研究肿瘤负荷在肿瘤侵袭性中的作用，以及它与癌症干细胞（CSC）标志物水平和IL-6信号传导的相关性。此外，对167份前列腺癌活检标本进行了IL-6和CD44水平与临床患者特征相关性分析。临床前模型的数据显示，更大的肿瘤负荷与更具侵袭性的肿瘤生长相关，并增加了CD44表达。通过细胞实验和原位肿瘤模型，我们发现CD44+前列腺癌细胞具有CSC样特性、增强的上皮-间质转化（EMT）和更具免疫抑制性的微环境。基于临床样本的体外检测，IL-6和CD44水平之间存在显著相关性。阻断IL-6/STAT3信号传导可在体外和体内减弱CD44的表达、CSC样特性和侵袭性肿瘤行为。总之，CD44表达与前列腺癌的肿瘤侵袭性显著相关，IL-6信号的激活导致了诱导CD44表达的合适微环境。根据我们的研究，肿瘤负荷降低与微环境中IL-6信号减弱和肿瘤排斥增强相关，这可能介导了积极局部治疗在临床上应用的益处。
