Long Yuqing, Dan Yuxi, Jiang Yao, Ma Jing, Zhou Tao, Fang Liaoqiong, Wang Zhibiao
State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China.
Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China.
Biology (Basel). 2024 Oct 27;13(11):873. doi: 10.3390/biology13110873.
Angiogenesis plays a crucial role in the growth of colorectal cancer (CRC). Recent studies have identified extracellular vesicles (EVs) in the tumor microenvironment as important mediators of cell-to-cell communication. However, the specific role and mechanisms of CRC-derived EVs in regulating tumor angiogenesis remain to be further investigated.
EVs were isolated from the conditioned medium of the CRC cells using ultracentrifugation. We investigated the effects of HT-29-derived EVs on tumor growth and angiogenesis in a subcutaneous HT-29 CRC tumor model in mice. Additionally, we evaluated the impact of HT-29-derived EVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, bioinformatics analysis was performed to identify relevant signaling pathways, and pathway inhibitors were used to block the activation of these pathways, aiming to elucidate their roles in angiogenesis.
We found that HT-29-derived EVs can promote tumor growth and angiogenesis in vivo, as well as significantly enhance the proliferation, migration, and tube formation of HUVECs. Bioinformatics analysis revealed that HT-29-derived EVs may regulate angiogenesis through the JAK/STAT3 signaling pathway. Specifically, we observed that CRC-derived EVs promoted the phosphorylation of STAT3 (p-STAT3) and the expression of VEGFA in the nucleus of HUVECs. Treatment with the STAT3 inhibitor Stattic reduced the nuclear expression of p-STAT3, which impaired its function as a transcription factor, thereby inhibiting VEGFA expression and the pro-angiogenic effects of CRC-derived EVs.
EVs derived from CRC cells promote CRC tumor angiogenesis by regulating VEGFA through the JAK/STAT3 pathway in endothelial cells.
血管生成在结直肠癌（CRC）的生长中起着关键作用。最近的研究已确定肿瘤微环境中的细胞外囊泡（EVs）是细胞间通讯的重要介质。然而，CRC来源的EVs在调节肿瘤血管生成中的具体作用和机制仍有待进一步研究。
使用超速离心法从CRC细胞的条件培养基中分离出EVs。我们在小鼠皮下HT-29 CRC肿瘤模型中研究了HT-29来源的EVs对肿瘤生长和血管生成的影响。此外，我们评估了HT-29来源的EVs对人脐静脉内皮细胞（HUVECs）增殖、迁移和管腔形成的影响。随后，进行生物信息学分析以鉴定相关信号通路，并使用通路抑制剂阻断这些通路的激活，旨在阐明它们在血管生成中的作用。
我们发现HT-29来源的EVs可以促进体内肿瘤生长和血管生成，并显著增强HUVECs的增殖、迁移和管腔形成。生物信息学分析表明，HT-29来源的EVs可能通过JAK/STAT3信号通路调节血管生成。具体而言，我们观察到CRC来源的EVs促进了HUVECs细胞核中STAT3的磷酸化（p-STAT3）和VEGFA的表达。用STAT3抑制剂Stattic处理可降低p-STAT3的核表达，这损害了其作为转录因子的功能，从而抑制了VEGFA的表达以及CRC来源的EVs的促血管生成作用。
CRC细胞来源的EVs通过在内皮细胞中通过JAK/STAT3途径调节VEGFA来促进CRC肿瘤血管生成。
