NEO212 Inhibits Migration and Invasion of Glioma Stem Cells.
NEO212 Inhibits Migration and Invasion of Glioma Stem Cells.
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DOI：
10.1158/1535-7163.mct-17-0591
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发表时间：
2018-03
影响因子：
5.7
通讯作者：
Hofman FM
中科院分区：
文献类型：
--
作者：
Marín-Ramos NI;Thein TZ;Cho HY;Swenson SD;Wang W;Schönthal AH;Chen TC;Hofman FM
多形性胶质母细胞瘤是一种恶性脑肿瘤，以其广泛的血管分布、侵袭性和高度侵袭性而闻名，这表明细胞迁移在肿瘤进展中起着重要作用。GBM的不良预后与高肿瘤复发率和对标准化疗替莫唑胺（TMZ）的耐药性相关。新型化合物NEO 212是TMZ和紫苏醇（POH）的缀合物，已被证明对胶质瘤干细胞（GSC）的细胞毒性比TMZ高10倍，并且对TMZ耐药肿瘤细胞具有活性。在这项研究中，我们发现NEO 212减少了间充质USC 02和前神经USC 04人群中患者来源的GSC原代培养物的迁移和侵袭。NEO 212减少迁移和侵袭的机制似乎与其DNA烷基化作用无关，DNA烷基化作用在治疗的最初几个小时内引起细胞毒性，并且与FAK/Src信号通路的减少有关，TMZ没有表现出这种作用。NEO 212还减少基质金属蛋白酶MMP 2和MMP 9的产生，这对GSC侵袭至关重要。上皮和间充质标志物的基因表达分析表明，NEO 212增加了上皮样特征的表达，表明上皮向间充质转化（EMT）过程的逆转。此外，在体内原位胶质瘤模型中，NEO 212通过减少GSC的侵袭来减少肿瘤进展，从而增加小鼠的存活时间。这些研究表明，NEO 212除了细胞毒性外，还可以有效地减少GSC中的迁移和侵袭，从而在减少侵袭和恶性胶质瘤进展方面显示出显著的临床价值。
Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10 fold more cytotoxic to glioma stem cells (GSCs) than TMZ, and is active against TMZ-resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition (EMT) process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression.