Yang Yang, Qiang Cheng, Jie Zhu, Ce Han, Yan Huang, Xiu-Bin Li, Wen-Mei Fan, Xu Zhang, Yu Gao
Department of Urology, the third Medical Centre, Chinese PLA General Hospital, Beijing, China.
Medical School of Chinese PLA, Beijing, China.
Cell Death Discov. 2025 Apr 25;11(1):198. doi: 10.1038/s41420-025-02434-8.
The interaction between tumor-derived exosomes and stroma plays a crucial role in tumor progression. However, the mechanisms through which tumor cells influence stromal changes are not yet fully understood. In our study, through single-cell sequencing analysis of clear cell renal cell carcinoma tissues at varying stages of progression, we determined that the proportion of cancer-associated fibroblasts (CAFs) in advanced renal cell carcinoma tissues was notably higher compared to localized renal cell carcinoma tissues. Comparison of transcriptome sequencing and energy metabolism tests between CAFs primarily isolated from advanced renal cell carcinoma tissues and normal fibroblasts (NFs) revealed the occurrence of the Warburg effect during the fibroblast activation process. Additionally, we observed an increase in glucose transporter GLUT1 expression, total reactive oxygen species (ROS) levels, lactic acid production, and subsequent excretion of excess lactic acid through monocarboxylate transporter-4 (MCT4) in CAFs. Interestingly, renal cancer cells were found to uptake lactic acid via MCT1 upon interaction with CAFs, thereby enhancing their malignant phenotypes. Furthermore, the down-regulation of PANK3 induced by exosomes derived from renal cancer cells was identified as a crucial step in fibroblast activation. These findings indicate that exosomes play a role in facilitating intercellular communication between renal cancer cells and fibroblasts. Targeting this communication pathway could potentially offer new strategies for the prevention and treatment of advanced renal cell carcinoma.
肿瘤来源的外泌体与基质之间的相互作用在肿瘤进展中起着至关重要的作用。然而，肿瘤细胞影响基质变化的机制尚未完全阐明。在我们的研究中，通过对不同进展阶段的透明细胞肾细胞癌组织进行单细胞测序分析，我们确定晚期肾细胞癌组织中癌相关成纤维细胞（CAFs）的比例明显高于局限性肾细胞癌组织。对主要从晚期肾细胞癌组织中分离出的CAFs与正常成纤维细胞（NFs）之间的转录组测序和能量代谢测试的比较显示，在成纤维细胞激活过程中发生了瓦伯格效应。此外，我们观察到CAFs中葡萄糖转运蛋白GLUT1的表达增加、总活性氧（ROS）水平升高、乳酸产生增加，随后通过单羧酸转运蛋白-4（MCT4）排出过量乳酸。有趣的是，发现肾癌细胞在与CAFs相互作用时通过MCT1摄取乳酸，从而增强其恶性表型。此外，由肾癌细胞衍生的外泌体诱导的PANK3下调被确定为成纤维细胞激活的关键步骤。这些发现表明外泌体在促进肾癌细胞与成纤维细胞之间的细胞间通讯中发挥作用。靶向这一通讯途径可能为晚期肾细胞癌的预防和治疗提供新策略。
