STAT3 Blockade Inhibits Radiation-Induced Malignant Progression in Glioma.
STAT3 Blockade Inhibits Radiation-Induced Malignant Progression in Glioma.
复制标题
DOI：
10.1158/0008-5472.can-14-3331
复制
发表时间：
2015-10-15
期刊：
影响因子：
11.2
通讯作者：
Persson AI
中科院分区：
文献类型：
--
作者：
Lau J;Ilkhanizadeh S;Wang S;Miroshnikova YA;Salvatierra NA;Wong RA;Schmidt C;Weaver VM;Weiss WA;Persson AI
恶性进展通常与间充质表型和不良预后相关。为了测试放射治疗是否促进间质转化，我们照射了高级别胶质瘤基因工程小鼠模型中产生的前神经肿瘤。头部电离辐射诱导了肿瘤中强大而持久的前神经向间质转化。来自小鼠和人类肿瘤的原发性前神经高级别胶质瘤细胞的辐射也诱导了持续的细胞-内在间充质转化，与增加的侵袭性和对烷化剂替莫唑胺的抗性相关。转录因子STAT 3被激活，以响应辐射，阻断STAT 3废除间充质转化和JAK 2抑制剂与辐射延长小鼠的生存期的组合治疗。我们的数据表明，临床JAK 2抑制剂应与放射治疗联合应用于前神经高级别胶质瘤患者，以阻断复发时耐药间质肿瘤的出现。
Malignant progression is often associated with a mesenchymal phenotype and poor prognosis. To test whether radiotherapy promotes a mesenchymal transition, we irradiated proneural tumors arising in a genetically engineered mouse model for high-grade glioma. Cranial ionizing radiation induced a robust and durable proneural-to-mesenchymal transition in tumors. Radiation of primary proneural high-grade glioma cells derived from mouse and human tumors also induced a sustained cell-intrinsic mesenchymal transition, associated with increased invasiveness and resistance to the alkylating agent temozolomide. The transcription factor STAT3 was activated in response to irradiation, and blockade of STAT3 abrogated the mesenchymal transition and combination treatment of JAK2 inhibitors with radiation extended survival in mice. Our data suggest that clinical JAK2 inhibitors should be tested in conjunction with radiation in patients with proneural high-grade glioma, to block emergence of therapy-resistant mesenchymal tumors at relapse.