Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, 04-141 Warsaw, Poland.
Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland.
Int J Mol Sci. 2022 Jan 21;23(3):1166. doi: 10.3390/ijms23031166.
2D culture as a model for drug testing often turns to be clinically futile. Therefore, 3D cultures (3Ds) show potential to better model responses to drugs observed in vivo. In preliminary studies, using melanoma (B16F10) and renal (RenCa) cancer, we confirmed that 3Ds better mimics the tumor microenvironment. Here, we evaluated how the proposed 3D mode of culture affects tumor cell susceptibility to anti-cancer drugs, which have distinct mechanisms of action (everolimus, doxorubicin, cisplatin). Melanoma spheroids showed higher resistance to all used drugs, as compared to 2D. In an RCC model, such modulation was only observed for doxorubicin treatment. As drug distribution was not affected by the 3D shape, we assessed the expression of MDR1 and mTor. Upregulation of MDR1 in RCC spheroids was observed, in contrast to melanoma. In both models, mTor expression was not affected by the 3D cultures. By NGS, 10 genes related with metabolism of xenobiotics by cytochrome p450 were deregulated in renal cancer spheroids; 9 of them were later confirmed in the melanoma model. The differences between 3D models and classical 2D cultures point to the potential to uncover new non-canonical mechanisms to explain drug resistance set by the tumor in its microenvironment.
2D 培养作为药物测试的模型通常在临床上是无效的。因此，3D 培养（3D 培养）显示出更好地模拟体内观察到的药物反应的潜力。在初步研究中，使用黑色素瘤（B16F10）和肾（RenCa）癌，我们证实 3D 培养更好地模拟了肿瘤微环境。在这里，我们评估了所提出的 3D 培养模式如何影响肿瘤细胞对具有不同作用机制的抗癌药物的敏感性（依维莫司、多柔比星、顺铂）。与 2D 相比，黑色素瘤球体对所有使用的药物表现出更高的耐药性。在 RCC 模型中，仅观察到多柔比星治疗时出现这种调节。由于药物分布不受 3D 形状的影响，我们评估了 MDR1 和 mTor 的表达。在 RCC 球体中观察到 MDR1 的上调，而在黑色素瘤中则没有。在这两种模型中，mTor 的表达不受 3D 培养的影响。通过 NGS，在肾癌球体中发现与细胞色素 p450 代谢外来物质有关的 10 个基因失调；其中 9 个在黑色素瘤模型中得到了进一步证实。3D 模型与经典 2D 培养之间的差异表明，有可能揭示新的非典型机制，以解释肿瘤在其微环境中产生的耐药性。
