Treatment in children with high-risk neuroblastoma remains largely unsuccessful due to the development of metastases and drug resistance. The biological complexity of these tumors and their microenvironment represent one of the many challenges to face. Matrix glycoproteins such as vitronectin act as bridge elements between extracellular matrix and tumor cells and can promote tumor cell spreading. In this study, we established through a clinical cohort and preclinical models that the interaction of vitronectin and its ligands, such as α_v integrins, are related to the stiffness of the extracellular matrix in high-risk neuroblastoma. These marked alterations found in the matrix led us to specifically target tumor cells within these altered matrices by employing nanomedicine and combination therapy. Loading the conventional cytotoxic drug etoposide into nanoparticles significantly increased its efficacy in neuroblastoma cells. We noted high synergy between etoposide and cilengitide, a high-affinity cyclic pentapeptide α_v integrin antagonist. The results of this study highlight the need to characterize cell-extracellular matrix interactions, to improve patient care in high-risk neuroblastoma.

由于转移和耐药性的发展，高危神经母细胞瘤儿童的治疗在很大程度上仍然不成功。这些肿瘤及其微环境的生物学复杂性代表了要面临的众多挑战之一。玻连蛋白等基质糖蛋白作为细胞外基质和肿瘤细胞之间的桥梁元件，可以促进肿瘤细胞的扩散。在本研究中，我们通过临床队列和临床前模型建立了玻连蛋白与其配体（如 α _v整合素与高危神经母细胞瘤细胞外基质的硬度有关。在基质中发现的这些显着改变使我们通过采用纳米医学和联合治疗来特异性靶向这些改变基质中的肿瘤细胞。将传统的细胞毒性药物依托泊苷装载到纳米颗粒中，显着提高了其在神经母细胞瘤细胞中的疗效。我们注意到依托泊苷和西仑吉肽（一种高亲和力环状五肽 α _v整合素拮抗剂）之间的高度协同作用。这项研究的结果强调了表征细胞 - 细胞外基质相互作用的必要性，以改善高危神经母细胞瘤的患者护理。