Background:ATRTs and DIPGs are deadly pediatric brain tumors with poor prognosis. These tumors can develop resistance to chemotherapies, which may be significantly influenced by their microenvironment. Since astrocytes are the most abundant glial cell type in the brain microenvironment and may support tumor growth and chemoresistance, this study investigated the effects of induced pluripotent stem cell-derived astrocytes (iPSC-astrocytes) on cisplatin sensitivity in CHLA-05-ATRT and SF8628 (DIPG) cells. iPSCs provide an unlimited and standardized source of nascent astrocytes, which enables modeling the interaction between childhood brain tumor cells and iPSC-astrocytes within a controlled coculture system.Methods:To study the effects on tumor growth, the iPSC-astrocytes were cocultured with tumor cells. Additionally, the tumor cells were exposed to various concentrations of cisplatin to evaluate their chemosensitivity in the presence of astrocytes.Results:The paracrine interaction of iPSC-astrocytes with tumor cells upregulated astrocyte activation markers GFAP and STAT3 and promoted tumor cell proliferation. Moreover, the cisplatin treatment significantly decreased the viability of CHLA-05-ATRT and SF8628 cells. However, tumor cells exhibited reduced sensitivity to cisplatin in the coculture with iPSC-astrocytes. During cisplatin treatment, DIPG cells in particular showed upregulation of resistance markers, ERK1, STAT3, and MTDH, which are associated with enhanced proliferation and invasion. They also had increased expression of APEX1, which is involved in the base excision repair pathway following cisplatin-induced DNA damage.Conclusion:These findings underscore the significance of the tumor microenvironment in modulating tumor cell survival and chemosensitivity.
背景：非典型畸胎样横纹肌样瘤（ATRT）和弥漫内生型脑桥胶质瘤（DIPG）是预后极差的致命性儿童脑肿瘤。这些肿瘤可能对化疗药物产生耐药性，而肿瘤微环境可能在其中发挥重要调控作用。鉴于星形胶质细胞是脑微环境中数量最多的胶质细胞类型，且可能支持肿瘤生长和化疗耐药，本研究探讨了诱导多能干细胞来源的星形胶质细胞（iPSC-astrocytes）对CHLA-05-ATRT和SF8628（DIPG）细胞顺铂敏感性的影响。iPSCs为新生星形胶质细胞提供了无限且标准化的来源，使得在可控共培养系统中模拟儿童脑肿瘤细胞与iPSC-astrocytes的相互作用成为可能。 方法：为研究对肿瘤生长的影响，将iPSC-astrocytes与肿瘤细胞共培养。此外，将肿瘤细胞暴露于不同浓度的顺铂中，以评估其在星形胶质细胞存在下的化疗敏感性。 结果：iPSC-astrocytes与肿瘤细胞的旁分泌相互作用上调了星形胶质细胞活化标志物GFAP和STAT3的表达，并促进了肿瘤细胞增殖。顺铂处理显著降低了CHLA-05-ATRT和SF8628细胞的活力。然而，在与iPSC-astrocytes共培养时，肿瘤细胞对顺铂的敏感性降低。在顺铂处理期间，DIPG细胞尤其表现出耐药标志物ERK1、STAT3和MTDH的上调，这些标志物与增殖和侵袭能力增强相关。同时，APEX1的表达也增加，该蛋白参与顺铂诱导DNA损伤后的碱基切除修复通路。 结论：这些发现强调了肿瘤微环境在调控肿瘤细胞存活和化疗敏感性方面的重要性。
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