Background: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.Methods: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: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.Conclusions: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.
背景：胃癌是一种高度侵袭性的疾病，常因对紫杉醇等化疗药物产生耐药性而复杂化。紫杉醇通过靶向微管诱导细胞凋亡。耐药性的产生涉及复杂的分子机制，包括促血管生成因子（VEGFA、ANG-2）的过表达、生存通路（PDGFRβ、PPARγ）的激活，以及由VIM、E-CAD、N-CAD和FLOT-1等蛋白驱动的上皮-间质转化。细胞外基质受COL1A1调控并受PPARγ影响，可作为药物渗透的物理屏障。小细胞外囊泡已成为细胞间通讯的关键介质，并可能影响这些耐药通路。 方法：本研究探讨了从接受雷莫西尤单抗和紫杉醇治疗的转移性胃癌患者中分离的小细胞外囊泡的作用。根据无进展生存期将患者分为快速进展组和疾病控制组。将这些患者的小细胞外囊泡应用于HCEC-1CT和HEPA-RG细胞系。通过细胞活力测定、基因和蛋白表达分析以及生物信息学研究，评估小细胞外囊泡对耐药相关标志物的影响。 结果：结果显示，疾病控制组患者的小细胞外囊泡降低了与耐药性相关的标志物表达，而快速进展组患者的小细胞外囊泡则增加了这些标志物的表达，促进了血管生成、上皮-间质转化和细胞外基质重塑。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，小细胞外囊泡调节炎症、细胞外基质动态和上皮-间质转化通路。 结论：综上所述，转移性胃癌患者的小细胞外囊泡显著影响化疗耐药性和肿瘤进展。靶向小细胞外囊泡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。
肿瘤(癌症)患者之家