Alievi Anderson Lucas, Teixeira Michelli Ramires, da Costa Vitor Rodrigues, Kerkis Irina, Araldi Rodrigo Pinheiro
Postgraduate Program in Endocrinology and Metabology, Paulista School of Medicine of the Federal University of São Paulo (EPM/UNIFESP), São Paulo 04023-062, SP, Brazil.
Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil.
Int J Mol Sci. 2025 Jul 4;26(13):6443. doi: 10.3390/ijms26136443.
Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with poor prognosis and limited treatment options. Precision oncology seeks personalized therapies that selectively modulate tumor behavior, which is critical for improving patient outcomes. In this study, we evaluated the therapeutic potential of human dental pulp stem cell-derived extracellular vesicles (hDPSC-EVs) in three ATC cell lines (8505C, HTH83, KTC-2). Fluorescence and confocal microscopy confirmed the efficient, time-dependent internalization of hDPSC-EVs by ATC cells, with increased fluorescence intensity over 48 h. Functional assays revealed the selective inhibition of migration and invasion in a cell line-dependent manner, without affecting cell proliferation, viability, or tumorigenic traits, indicating a non-cytotoxic, context-specific modulation of tumor behavior. After 72 h of EV treatment, targeted qPCR of 92 cancer-related genes showed the strongest response in 8505C cells (24 genes; 16 up, 8 down), moderate changes in KTC-2 (16 genes; 14 up, 2 down), and few alterations in HTH83 (6 genes; 4 up, 2 down). Across all lines, emerged as a context-dependent target, downregulated in 8505C but upregulated in the other two. No broad pathway enrichment was observed, indicating the fine-tuning of key networks rather than wholesale reprogramming. Despite variations across cell lines, hDPSC-EVs consistently demonstrated no impact on cell proliferation and no evidence of cytotoxicity or tumorigenic behavior, with no adverse outcomes. These findings provide preclinical evidence for hDPSC-EVs as a promising, safe, and targeted therapeutic platform in precision oncology, particularly for aggressive cancers, like ATC, warranting further exploration in preclinical and clinical studies.
间变性甲状腺癌（ATC）是一种侵袭性很强的恶性肿瘤，预后较差，治疗选择有限。精准肿瘤学旨在寻找能够选择性调节肿瘤行为的个性化疗法，这对于改善患者预后至关重要。在本研究中，我们评估了人牙髓干细胞衍生的细胞外囊泡（hDPSC-EVs）对三种ATC细胞系（8505C、HTH83、KTC-2）的治疗潜力。荧光和共聚焦显微镜证实了ATC细胞对hDPSC-EVs的高效、时间依赖性内化，荧光强度在48小时内增加。功能分析显示，hDPSC-EVs以细胞系依赖性方式选择性抑制迁移和侵袭，而不影响细胞增殖、活力或致瘤特性，表明对肿瘤行为具有非细胞毒性、背景特异性调节作用。EV处理72小时后，对92个癌症相关基因进行靶向qPCR分析，结果显示8505C细胞反应最强（24个基因；16个上调，8个下调），KTC-2细胞有中度变化（16个基因；14个上调，2个下调），HTH83细胞变化较少（6个基因；4个上调，2个下调）。在所有细胞系中， 作为一个背景依赖性靶点出现，在8505C细胞中下调，但在其他两个细胞系中上调。未观察到广泛的通路富集，表明是关键网络的微调而非全面重编程。尽管各细胞系存在差异，但hDPSC-EVs始终显示对细胞增殖无影响，也没有细胞毒性或致瘤行为的证据，且无不良后果。这些发现为hDPSC-EVs作为精准肿瘤学中一个有前景、安全且靶向的治疗平台提供了临床前证据，特别是对于像ATC这样的侵袭性癌症，值得在临床前和临床研究中进一步探索。
