Targeting cancer stem cells through L1CAM suppresses glioma growth.
Targeting cancer stem cells through L1CAM suppresses glioma growth.
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DOI：
10.1158/0008-5472.can-08-1079
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Rich JN
中科院分区：
文献类型：
--
作者：
Bao S;Wu Q;Li Z;Sathornsumetee S;Wang H;McLendon RE;Hjelmeland AB;Rich JN
恶性神经胶质瘤是一种极其致命的癌症，表现出惊人的细胞异质性。高度致瘤性神经胶质瘤肿瘤亚群，称为癌症干细胞或肿瘤起始细胞，促进治疗抗性和肿瘤血管生成。因此，靶向癌症干细胞可能会改善患者的生存率。我们询问了神经细胞粘附分子L1 CAM在神经胶质瘤干细胞中的作用，因为L1 CAM调节脑发育并在神经胶质瘤中表达。L1 CAM+和CD 133+细胞在胶质瘤中共分离，并且CD 133+胶质瘤细胞中的L1 CAM水平高于正常神经祖细胞。在CD 133+胶质瘤细胞中使用慢病毒介导的短发夹RNA（shRNA）干扰靶向L1 CAM有效地破坏神经球形成，诱导凋亡，并特异性地抑制胶质瘤干细胞的生长。我们确定了一种新的机制，L1 CAM调节细胞存活的L1 CAM敲低降低表达的基本螺旋-环-螺旋转录因子Olig 2和上调的p21 WAF 1/CIP 1肿瘤抑制在CD 133+胶质瘤细胞。为了确定靶向L1 CAM是否足以减少体内胶质瘤干细胞肿瘤生长，我们在注射到免疫功能低下的小鼠或直接注射到已建立的肿瘤之前靶向胶质瘤细胞中的L1 CAM。在每个胶质瘤异种移植模型中，体内靶向L1 CAM表达的shRNA抑制了肿瘤生长并增加了荷瘤动物的存活率。总之，这些数据表明，L1 CAM是维持CD 133+胶质瘤细胞在体外和体内的生长和存活所必需的，并且L1 CAM可能代表用于改善恶性胶质瘤和其他脑肿瘤的治疗的癌症干细胞特异性治疗靶点。
Malignant gliomas are extremely lethal cancers that display striking cellular heterogeneity. A highly tumorigenic glioma tumor subpopulation, termed cancer stem cells or tumor-initiating cells, promotes therapeutic resistance and tumor angiogenesis. Therefore, targeting cancer stem cells may improve patient survival. We interrogated the role of a neuronal cell adhesion molecule, L1CAM, in glioma stem cells as L1CAM regulates brain development and is expressed in gliomas. L1CAM+ and CD133+ cells co-segregated in gliomas, and levels of L1CAM were higher in CD133+ glioma cells than normal neural progenitors. Targeting L1CAM using lentiviral-mediated short hairpin RNA (shRNA) interference in CD133+ glioma cells potently disrupted neurosphere formation, induced apoptosis, and inhibited growth specifically in glioma stem cells. We identified a novel mechanism for L1CAM regulation of cell survival as L1CAM knockdown decreased expression of the basic helix-loop-helix transcription factor Olig2 and up-regulated the p21WAF1/CIP1 tumor suppressor in CD133+ glioma cells. To determine if targeting L1CAM was sufficient to reduce glioma stem cell tumor growth in vivo, we targeted L1CAM in glioma cells prior to injection into immunocompromised mice or directly in established tumors. In each glioma xenograft model, shRNA targeting of L1CAM expression in vivo suppressed tumor growth and increased the survival of tumor-bearing animals. Together, these data demonstrate that L1CAM is required for maintaining the growth and survival of CD133+ glioma cells both in vitro and in vivo, and L1CAM may represent a cancer stem cell specific therapeutic target for improving the treatment of malignant gliomas and other brain tumors.