Panzetta Giorgia, Schirizzi Annalisa, Balestra Francesco, De Luca Maria, Depalo Nicoletta, Rizzi Federica, Ricci Angela Dalia, De Leonardis Giampiero, Lotesoriere Claudio, Giannelli Gianluigi, D'Alessandro Rosalba, Scavo Maria Principia
Laboratory of Molecular Medicine, National Institute of Gastroenterology, IRCCS "S. de Bellis" Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy.
Laboratory of Experimental Oncology, National Institute of Gastroenterology, IRCCS "S. de Bellis" Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy.
Cancers (Basel). 2025 Apr 18;17(8):1360. doi: 10.3390/cancers17081360.
Gastric cancer (GC) is a highly aggressive disease often complicated by resistance to chemotherapy agents like paclitaxel (PTX), which targets microtubules to induce apoptosis. Resistance arises through complex molecular mechanisms, including the overexpression of pro-angiogenic factors (VEGFA, ANG-2), activation of survival pathways (PDGFRβ, PPARγ), and epithelial-mesenchymal transition (EMT) driven by proteins such as VIM, E-CAD, N-CAD, and FLOT-1. The extracellular matrix (ECM), regulated by COL1A1 and influenced by PPARγ, acts as a physical barrier to drug penetration. Small extracellular vesicles (sEVs) have emerged as critical mediators of intercellular communication and may influence these resistance pathways. This study investigated the role of sEVs isolated from metastatic GC patients treated with Ramucirumab and PTX. Patients were stratified by progression-free survival (PFS) into rapidly progressing (RP) and controlled disease (CD) groups. sEVs from these patients were applied to HCEC-1CT and HEPA-RG cell lines. Cell viability assays, gene and protein expression analyses, and bioinformatic studies were conducted to assess the impact of sEVs on resistance-related markers. Results showed that sEVs from CD patients reduced the expression of markers associated with drug resistance, while sEVs from RP patients increased these markers, promoting angiogenesis, EMT, and ECM remodeling. These changes correlated with enhanced cell survival and resistance phenotypes. Bioinformatic analyses confirmed that sEVs modulate inflammation, ECM dynamics, and EMT pathways. In conclusion, sEVs from metastatic GC patients significantly influence chemoresistance and tumor progression. Targeting sEV-mediated signaling may offer novel therapeutic strategies to overcome resistance and improve treatment outcomes in gastric cancer.
胃癌（GC）是一种侵袭性很强的疾病，常因对紫杉醇（PTX）等化疗药物产生耐药性而变得复杂，紫杉醇通过靶向微管诱导细胞凋亡。耐药性通过复杂的分子机制产生，包括促血管生成因子（VEGFA、ANG-2）的过度表达、生存途径（PDGFRβ、PPARγ）的激活以及由波形蛋白（VIM）、E-钙黏蛋白（E-CAD）、N-钙黏蛋白（N-CAD）和 flotillin-1（FLOT-1）等蛋白质驱动的上皮-间质转化（EMT）。由 I 型胶原蛋白α1（COL1A1）调节并受 PPARγ影响的细胞外基质（ECM），作为药物渗透的物理屏障。小细胞外囊泡（sEVs）已成为细胞间通讯的关键介质，并可能影响这些耐药途径。本研究调查了从接受雷莫西尤单抗和 PTX 治疗的转移性 GC 患者中分离出的 sEVs 的作用。患者根据无进展生存期（PFS）分为快速进展（RP）组和疾病控制（CD）组。将这些患者的 sEVs 应用于 HCEC-1CT 和 HEPA-RG 细胞系。进行细胞活力测定、基因和蛋白质表达分析以及生物信息学研究，以评估 sEVs 对耐药相关标志物的影响。结果显示，CD 患者的 sEVs 降低了与耐药性相关标志物的表达，而 RP 患者的 sEVs 则增加了这些标志物，促进血管生成、EMT 和 ECM 重塑。这些变化与增强的细胞存活和耐药表型相关。生物信息学分析证实，sEVs 调节炎症、ECM 动态和 EMT 途径。总之，转移性 GC 患者的 sEVs 显著影响化疗耐药性和肿瘤进展。靶向 sEV 介导的信号传导可能为克服耐药性和改善胃癌治疗结果提供新的治疗策略。
