Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling
Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling
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DOI：
10.1002/em.21988
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发表时间：
2016-06-01
影响因子：
2.8
通讯作者：
Limoli, Charles L.
中科院分区：
文献类型：
--
作者：
Baulch, Janet E.;Geidzinski, Erich;Limoli, Charles L.
恶性胶质瘤是动态相互作用细胞的异质群体。基因组和转录的变化定义了这种细胞层次结构，并允许某些肿瘤细胞共同选择代谢机制，并采用促进细胞重编程的基因表达谱。由此产生的特权亚群的扩大可以迅速适应微环境压力，最终影响肿瘤对治疗干预的反应。在这项研究中，原发性胶质瘤受到急性或慢性照射，并分析了从照射和未照射的胶质瘤细胞中分离的分泌微泡治疗前后生存参数、氧化应激、基因表达和细胞侵袭的变化。我们发现，暴露于电离辐射的原发性胶质瘤发生代谢变化，增加氧化应激，改变基因表达，影响细胞分泌微泡的含量和对细胞分泌微泡的反应。与急性辐射模式相比，慢性辐射诱导的变化加剧，并通过增强参与分化和多能性的关键转录因子和调节因子（SOX2, POU3F2, SALL2, OLIG2， NANOG, POU5F1v1, MSI1）的表达促进细胞重编程。照射还影响了由细胞分泌的微泡介导的旁分泌信号的变化，从而显著改变了靶细胞的表型。用微囊泡治疗原发性胶质瘤表现出增强的放射抗性，而长期照射胶质瘤的微囊泡治疗通过诱导基质金属蛋白酶II活性增加而促进了侵袭。总之，我们的数据描述了原发性胶质瘤细胞的复杂辐射反应，涉及代谢和转录变化，改变辐射敏感性并诱导侵袭行为。这些重要的变化可以促进肿瘤的生长和复发，并混淆了旨在预防疾病进展的干预措施。环绕。中国生物医学工程学报，2016,37(2):444 - 444。(c) 2015 Wiley期刊公司
Malignant gliomas are heterogeneous populations of dynamically interacting cells. Genomic and transcriptional changes define this cellular hierarchy and allow certain tumor cells to co-opt metabolic machinery and adopt gene expression profiles that promote cellular reprogramming. Resultant expansion of privileged subpopulations can then rapidly adapt to microenvironmental stress that ultimately influence tumor response to therapeutic intervention. In this study, primary gliomas were subjected to acute or chronic irradiation and analyzed for changes in survival parameters, oxidative stress, gene expression, and cell invasion before and after treatment with secreted microvesicles isolated from irradiated and nonirradiated glioma cells. We found that primary gliomas exposed to ionizing radiation undergo metabolic changes that increase oxidative stress, alter gene expression, and affect the contents of and response to cellular secreted microvesicles. Radiation-induced changes were exacerbated under chronic as compared to acute irradiation paradigms and promoted cellular reprogramming through enhanced expression of key transcription factors and regulators involved in differentiation and pluripotency (SOX2, POU3F2, SALL2, OLIG2, NANOG, POU5F1v1, MSI1). Irradiation also affected changes in paracrine signaling mediated by cellular secreted microvesicles that significantly altered target cell phenotype. Primary gliomas treated with microvesicles exhibited increased radioresistance and treatment with microvesicles from chronically irradiated gliomas promoted invasion via induction of increased matrix metalloproteinase II activity. Together, our data describe a complex radiation response of primary glioma cells involving metabolic and transcriptional changes that alter radiation sensitivity and induce invasive behavior. These important changes can contribute to tumor growth and recurrence, and confound interventions designed to forestall disease progression. Environ. Mol. Mutagen. 57:405-415, 2016. (c) 2015 Wiley Periodicals, Inc.