Survival and Proliferation of Neural Progenitor-Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism.
Survival and Proliferation of Neural Progenitor-Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism.
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DOI：
10.1158/1078-0432.ccr-15-2888
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Castro MG
中科院分区：
文献类型：
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作者：
Calinescu AA;Yadav VN;Carballo E;Kadiyala P;Tran D;Zamler DB;Doherty R;Srikanth M;Lowenstein PR;Castro MG
胶质母细胞瘤治疗失败的一个可能原因是胶质瘤干细胞样细胞（GSLC）的持续存在，这些细胞对目前采用的治疗具有高度抗性。我们发现CXCL 12在神经前体细胞（NPC）衍生的胶质瘤细胞中具有最高表达。分析了NPC衍生的GBM的发展和分子特征，并测试了阻断CXCL 12的治疗效果。通过使用睡美人转座酶方法将DNA注射到新生小鼠的侧脑室中来诱导肿瘤。在疾病进展期间分析组织学和GSLC标志物的表达。分析了药物（普乐沙福）或CXCR 4遗传抑制治疗后的生存率。产生原代神经球并分析其增殖、凋亡和调节存活和细胞周期进程的蛋白质的表达。由NPC诱导的肿瘤显示人GBM的组织学特征并表达GSLC的标志物。在体内，抑制CXCL 12/CXCR 4信号传导轴导致荷瘤动物的存活增加。在体外，CXCR 4阻断诱导细胞凋亡并抑制细胞周期进展，下调调节存活和增殖的分子，还阻断HIF-1α和CXCL 12的缺氧诱导。CXCL 12的外源性施用挽救了药物诱导的增殖降低。这项研究表明，CXCL 12/CXCR 4轴在缺氧应激下通过自分泌正反馈机制在GBM细胞中发挥作用，促进生存和细胞周期进展。我们的研究带来了新的机制见解，并鼓励进一步探索使用阻断CXCL 12的药物作为佐剂，以靶向缺氧诱导的GBM进展，预防对治疗的抵抗和疾病的复发。
One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs) which are highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPCs). The development and molecular signature of NPC derived GBMs were analyzed and the therapeutic effect of blocking CXCL12 was tested. Tumors were induced by injecting DNA into the lateral ventricle of neonatal mice, using the Sleeping Beauty transposase method. Histology and expression of GSLC markers were analyzed during disease progression. Survival upon treatment with pharmacologic (Plerixafor) or genetic inhibition of CXCR4 was analyzed. Primary neurospheres were generated and analyzed for proliferation, apoptosis and expression of proteins regulating survival and cell cycle progression. Tumors induced from NPCs display histological features of human GBM and express markers of GSLC. In vivo, inhibiting the CXCL12/CXCR4 signaling axis results in increased survival of tumor-bearing animals. In vitro, CXCR4 blockade induces apoptosis and inhibits cell cycle progression, downregulates molecules regulating survival and proliferation and also blocks the hypoxic-induction of HIF-1α and CXCL12. Exogenous administration of CXCL12 rescues the drug-induced decrease in proliferation. This study demonstrates that the CXCL12/CXCR4 axis operates in GBM cells under hypoxic stress via an autocrine positive feedback mechanism, which promotes survival and cell cycle progression. Our study brings new mechanistic insight and encourages further exploration of the use of drugs blocking CXCL12 as adjuvant agents to target hypoxia-induced GBM progression, prevent resistance to treatment and recurrence of the disease.