Targeting cancer stem cells for brain tumor therapy

描述（由申请人提供）：神经干细胞（NSC）向大脑病理区域迁移的能力强调了这些细胞作为大脑细胞替代和/或药物递送剂的潜在用途。恶性胶质瘤由癌症干细胞（CSC）组成，最近被证明是肿瘤的根源，目前使用的治疗方法是难治的。我们已经描述了使用原代小鼠胚胎NSC或骨髓源性神经干细胞（BM-NSC）作为细胞毒性或免疫刺激剂治疗浸润性胶质瘤的运载工具的有效性，并描述了胶质瘤倾向的机制。然而，这些研究是基于用胶质瘤细胞系建立的肿瘤模型。越来越多的证据表明，原代肿瘤细胞是研究肿瘤生物学和治疗策略的必要条件，而且比肿瘤细胞系更好。我们最近证明了原发性人胶质母细胞瘤含有csc。CSCs具有自我更新的特性，在体外具有多潜能，并且可以在体内启动脑肿瘤，概括其来源的原发肿瘤的表型。我们还发现BM-NSCs在体外可以向CSCs迁移，在体内也可以向CSCs引发的肿瘤迁移。这些发现促使我们进一步研究成人脑干细胞作为一种可行的细胞载体来靶向脑肿瘤CSCs并提供治疗。我们现在的目标是验证以下假设：1)BM-NSC向原发性脑肿瘤CSCs的迁移依赖于BM-NSCs质膜上CXCR4的表达。2)脑转移- nsc向脑肿瘤CSCs迁移主要是由于GFAP+和A2B5+星形细胞前体，而脑转移后的终末分化有利于脑转移- nsc的植入。3)用BM-NSCs靶向CSC可以(i)转化为治疗基因的靶向递送，（ii）在CSC异种移植模型中增加肿瘤控制并延长生存期。脑肿瘤是最具破坏性的肿瘤之一，尽管进行了积极的治疗，但往往会迅速致命。从人类脑肿瘤中鉴定出的脑肿瘤干细胞具有驱动肿瘤形成的独特能力，可以证明是肿瘤治疗的有效靶点。在这个提议中，我们将开发有效靶向癌症干细胞的治疗策略，并最终产生治疗脑肿瘤的新方法。

DESCRIPTION (provided by applicant): The capacity of neural stem cells (NSC) to migrate toward pathological areas of the brain underscores the potential use of these cells as agents for cell replacement and/or drug delivery in the brain. Malignant gliomas consist of cancer stem cells (CSC), which have been demonstrated recently as the roots of the tumor, being refractory to current employed therapies. We have described the efficacy of using primary murine fetal NSC or bone marrow-derived neural stem cells (BM-NSC) as delivery vehicles for cytotoxic or immunostimulatory agents to treat infiltrating glioma and have described a mechanism of glioma tropism. However, these studies were based on tumor models established with glioma cell lines. Increasing evidence indicates that primary tumor cells are necessary and better than tumor cell lines for studying tumor biology and therapeutic strategies. We have recently demonstrated that primary human glioblastomas contain CSCs. The CSCs have characteristics of self-renewal, are multipotential in vitro, and can initiate brain tumors in vivo, recapitulating the phenotypes of the primary tumors from which they were derived. We also found that BM-NSCs can migrate toward CSCs in vitro and CSCs initiated tumors in vivo. These findings lead us to pursue further studies with adult BM-NSCs as a viable source of cellular vectors to target brain tumor CSCs and deliver therapy. We now aim to test the hypotheses that: 1) BM-NSC migration toward CSCs of primary brain tumors is dependent on CXCR4 expression on the plasma membrane of BM-NSCs. 2) BM-NSC migration toward brain tumor CSCs is mainly due to GFAP+ and A2B5+ astrocytic precursors, while terminal differentiation favors engraftment of BM-NSC after intracranial transplantation. 3) Targeting CSCs with BM-NSCs can (i) translate into targeted delivery of therapeutic genes and (ii) increase tumor control and prolong survival in a CSC xenograft model. Brain tumors are among the most devastating tumors and are often rapidly fatal despite aggressive treatments. Brain tumor cancer stem cells identified from human brain tumors have the exclusive ability to drive tumor formation, and could prove an effective target for tumor therapy. In this proposal, we will develop therapeutic strategies that are effectively targeting cancer stem cells and will ultimately yield new approaches to treat brain tumors.