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中细胞替代和/或药物递送试剂的潜在用途。恶性神经胶质瘤由癌症干细胞（CSC）组成，其最近已被证明是肿瘤的根源，对当前采用的疗法是难治的。我们已经描述了使用原代鼠胎儿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的递送载体来治疗浸润性胶质瘤的功效，并描述了胶质瘤嗜性的机制。然而，这些研究是基于用神经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所必需的，并且比肿瘤细胞系更好。我们最近已经证明，原发性人类胶质母细胞瘤含有CSC。CSC具有自我更新的特性，在体外是多潜能的，并且可以在体内引发脑肿瘤，重现它们所来源的原发性肿瘤的表型。我们还发现，BM-NSCs可以在体外向CSC迁移，并且CSC可以在体内引发肿瘤。这些发现使我们进一步研究成人BM-NSC作为细胞载体的可行来源，以靶向脑肿瘤CSC并提供治疗。我们现在的目标是测试以下假设：1）BM-NSC向原发性脑肿瘤的CSC的迁移依赖于BM-NSC的质膜上的CXCR4表达。2)BM-NSC向脑肿瘤CSC迁移主要是由于GFAP+和A2B5+星形胶质细胞前体，而终末分化有利于颅内移植后BM-NSC的植入。3)用BM-NSC靶向CSC可以（i）转化为治疗性基因的靶向递送和（ii）增加肿瘤控制并延长CSC异种移植模型中的存活。脑肿瘤是最具破坏性的肿瘤之一，尽管进行了积极的治疗，但通常很快就会致命。从人类脑肿瘤中鉴定出的脑肿瘤癌症干细胞具有独特的驱动肿瘤形成的能力，并且可以证明是肿瘤治疗的有效靶点。在这项提案中，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.