PO.TB10.15 · 肿瘤生物学
肿瘤来源外泌体通过重编程肿瘤相关巨噬细胞促进肾癌进展
Tumor-derived exosomes promote renal cancer progression via reprogramming of tumor-associated macrophages
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摘要 Abstract
中文摘要
肾细胞癌（RCC）是最常见的肾癌类型，其进展在很大程度上依赖于肿瘤微环境（TME）这一复杂生态系统。TME中的一个关键细胞成分是肿瘤相关巨噬细胞（TAM），它常呈现促肿瘤的M2样表型，支持血管生成、侵袭和免疫抑制。本研究探讨了肿瘤来源外泌体（TDEs）在介导这一关键重编程事件中的作用。体外实验采用了人源（786-O肾癌细胞系和THP-1单核细胞）和小鼠（Renca RCC和RAW 264.7单核/巨噬细胞）细胞系。用RCC来源的外泌体处理巨噬细胞，并用其条件培养基（CM）处理亲本RCC细胞。功能实验表明，经外泌体教育的巨噬细胞CM显著增加了人和小鼠RCC细胞的增殖、迁移和侵袭。此外，Western blot和ELISA分析证实TDE处理成功重编程了巨噬细胞，导致细胞因子谱改变，提示向促肿瘤表型极化。在体内，使用SCID和BALB/c小鼠模型通过心内和肾内RCC注射评估了TDE教育的巨噬细胞CM的影响。生物发光成像（BLI）证实，与对照相比，来自外泌体处理巨噬细胞的CM显著增强了肿瘤进展和远处转移。总之，本研究鉴定肿瘤来源外泌体为有效将TAMs重编程为促肿瘤细胞的关键信号载体。这种外泌体介导的通讯促进了高度允许性的TME，导致肾癌进展和转移加速。这些发现突显TDE-TAM轴为减轻RCC恶性程度的有效治疗靶点。
查看英文原文 English abstract
Renal cell carcinoma (RCC), the most common type of kidney cancer, relies heavily on the complex ecosystem of the Tumor Microenvironment (TME) for its progression. A critical cellular component within the TME is the Tumor-Associated Macrophage (TAM), which often adopts a pro-tumor, M2-like phenotype that supports angiogenesis, invasion, and immune suppression. This study investigates the role of tumor-derived exosomes (TDEs) in mediating this critical reprogramming event. In vitro experiments utilized human (786-O renal cancer cell line and THP-1 monocytes) and mouse (Renca RCC and RAW 264.7 monocytes/macrophage) cell lines. The macrophages were treated with RCC-derived exosomes, and the conditioned medium (CM) was used to treat parental RCC cells. Functional assays demonstrated that exosome-educated macrophage CM significantly increased the proliferation, migration, and invasion of both human and mouse RCC cells. Furthermore, Western blot and ELISA analysis confirmed that TDE treatment successfully reprogrammed macrophages, leading to altered cytokine profiles indicative of polarization toward a pro-tumor phenotype. In vivo, the impact of the TDE-educated macrophage CM was assessed in SCID and BALB/c mouse models using intracardial and intrarenal RCC injections. Bioluminescence imaging (BLI) confirmed that CM from exosome-treated macrophages significantly enhanced tumor progression and distant metastasis compared to controls. In conclusion, this research identifies tumor-derived exosomes as critical signaling vectors that effectively reprogram TAMs into pro-tumorigenic cells. This exosome-mediated communication promotes a highly permissive TME, leading to accelerated renal cancer progression and metastasis. These findings highlight the TDE-TAM axis as a potent therapeutic target for mitigating RCC malignancy.
利益披露 Disclosure
J. Dai, None..
S. Kadomoto, None..
T. Robinson, None.