Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy.
Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy.
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DOI：
10.3389/fonc.2013.00028
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发表时间：
2013
影响因子：
4.7
通讯作者：
Gillespie GY
中科院分区：
文献类型：
--
作者：
Friedman GK;Raborn J;Kelly VM;Cassady KA;Markert JM;Gillespie GY
虽然多形性胶质母细胞瘤（GBM）是最常见的成人恶性脑肿瘤，但儿童期的GBM占儿童恶性脑肿瘤的不到10%，并且在表型和分子上与成人GBM不同。与成人患者相似，儿童高级别胶质瘤（HGGs）的预后仍然很差。此外，目前的治疗方法对发育中的大脑造成的神经毒性使小儿GBM的发病率和死亡率显著增加。不良结果归因于化疗和放疗耐药细胞亚群，称为“胶质瘤干细胞”（GSCs），“胶质瘤祖细胞”或“胶质瘤起始细胞”，它们具有启动和维持肿瘤的能力，并在常规治疗后重新填充复发肿瘤。未来儿科HGG的创新疗法必须能够根除这些治疗耐药的GSCs。溶瘤性单纯疱疹病毒（oHSV）经过基因工程改造，对正常细胞是安全的，并表达多种外源抗肿瘤治疗基因，在临床前研究中已被证明可以平等地感染和杀死GSCs和肿瘤细胞，同时保留正常脑细胞。在这篇综述中，我们讨论了儿童GSCs的独特方面，包括识别它们的标志物，它们所处的微环境，调节它们的信号通路，细胞耐药机制，以及靶向GSCs的方法，重点是有前途的治疗性基因工程oHSV。
While glioblastoma multiforme (GBM) is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs) remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed “glioma stem cells” (GSCs), “glioma progenitor cells,” or “glioma-initiating cells,” which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGG must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses (oHSV), genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oHSV.