Omura Naoki, Nonoguchi Naosuke, Fujishiro Takahiro, Park Yangtae, Ikeda Naokado, Kajimoto Yoshinaga, Hosomi Ryota, Yagi Ryokichi, Hiramatsu Ryo, Furuse Motomasa, Kawabata Shinji, Fukunaga Kenji, Kuroiwa Toshihiko, Nakano Ichiro, Wanibuchi Masahiko
Department of Neurosurgery and Endovascular Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki 569-8686, Osaka, Japan.
Department of Neurosurgery and Endovascular Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki 569-8686, Osaka, Japan.
Photodiagnosis Photodyn Ther. 2023 Mar;41:103119. doi: 10.1016/j.pdpdt.2022.103119. Epub 2022 Nov 4.
Cancer cells with stem cell-like features are generally more resistant to chemotherapy and radiotherapy than differentiated tumor cells. Thus, these cells tend to increase the propensity for tumor recurrence and metastasis. This study investigated the efficacy of 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) in destructing glioma stem cells (GSCs), including the mesenchymal subtype (MES-GSCs) demonstrated to have the lowest radio- and chemosensitivity.
Five high-grade glioma (HGG) GSC lines and derived differentiated glioma cell (DGC) lines were examined for protoporphyrin-IX (PpIX) expression using fluorescence-activated cell sorting (FACS) and then assessed for ALA-PDT sensitivity using cell viability assays. MES-GSCs surviving ALA-PDT were then isolated and evaluated for stem cell and mesenchymal marker expression levels (CD44, ALDH1A3, KLF4, nestin) by qRT-PCR. The ability of these surviving cells to form tumors was then examined using colony forming and by xenograft tumor assays in athymic mice. Finally, the relationship between PpIX expression level (high versus low) and ALA-PDT sensitivity was examined by FACS and colony forming assays.
ALA-PDT was effective against all GSC lines including MES-GSCs. MES-GSC lines exhibited higher PpIX expression than derived DGCs. Surviving MES-GSCs demonstrated lower stem cell marker expression and tumor forming potential than naive MES-GSCs. Higher PpIX production capacity by MES-GSCs was associated with greater colony forming ability, and ALA-PDT was more effective against MES-GSCs with greater PpIX accumulation.
ALA-PDT may be clinically effective against HGG by targeting GSCs, including MES-GSCs.
具有干细胞样特征的癌细胞通常比分化的肿瘤细胞对化疗和放疗更具抗性。因此，这些细胞往往会增加肿瘤复发和转移的倾向。本研究调查了5-氨基乙酰丙酸介导的光动力疗法（ALA-PDT）在破坏胶质瘤干细胞（GSCs）中的疗效，包括已证明具有最低放射和化学敏感性的间充质亚型（MES-GSCs）。
使用荧光激活细胞分选（FACS）检测5种高级别胶质瘤（HGG）GSC系和衍生的分化胶质瘤细胞（DGC）系中原卟啉-IX（PpIX）的表达，然后使用细胞活力测定评估ALA-PDT敏感性。然后分离出在ALA-PDT后存活的MES-GSCs，并通过qRT-PCR评估干细胞和间充质标志物表达水平（CD44、ALDH1A3、KLF4、巢蛋白）。然后使用集落形成和在无胸腺小鼠中的异种移植肿瘤试验检查这些存活细胞形成肿瘤的能力。最后，通过FACS和集落形成试验检查PpIX表达水平（高与低）与ALA-PDT敏感性之间的关系。
ALA-PDT对包括MES-GSCs在内的所有GSC系均有效。MES-GSC系比衍生的DGCs表现出更高的PpIX表达。存活的MES-GSCs与未处理的MES-GSCs相比，干细胞标志物表达和肿瘤形成潜力更低。MES-GSCs更高的PpIX产生能力与更大的集落形成能力相关，并且ALA-PDT对具有更大PpIX积累的MES-GSCs更有效。
ALA-PDT通过靶向GSCs，包括MES-GSCs，可能在临床上对HGG有效。
