Glioblastoma stem cell-derived pericytes and cancer invasion

摘要 胶质母细胞瘤(GBM)是最致命的原发脑癌，具有高度侵袭性和耐药性。 到目前的治疗方法。肿瘤侵袭和肿瘤复发在GBM患者中普遍存在 尽管接受了最大限度的治疗。一些治疗方法，如抗血管生成疗法，实际上改变了 肿瘤向更具侵袭性的表型生长。定义基础机制 治疗诱导的肿瘤侵袭和肿瘤再生长可能有助于改善GBM的治疗。 基底膜含有丰富的血管，由内皮细胞和周细胞组成。周细胞 在维持血管功能和血脑(肿瘤)屏障方面发挥关键作用。我们发现 基底膜中的大多数血管周细胞来自于胶质瘤干细胞， 高度可塑性的细胞亚群由自我更新、多潜能和肿瘤功能决定 传播。选择性靶向GSC来源的周细胞破坏肿瘤血管并有效地 抑制肿瘤生长，表明GSC来源的周细胞在支持 血管结构和功能促进肿瘤生长。此外，GSC来源的周细胞 在肿瘤周围脑部的血管亚群上被检测到，这表明这些肿瘤 周细胞具有向脑组织迁移的能力。我们最近利用细胞谱系进行的研究 示踪显示GSC来源的周细胞具有去分化为 能够生长肿瘤的GSCs。此外，GSC来源的周细胞对 目前的治疗表明，GSC来源的周细胞可能作为肿瘤的储存库- 起始细胞通过去分化为神经干细胞促进肿瘤侵袭和肿瘤复发 在治疗之后。因此，我们假设GSC来源的周细胞是储备癌细胞 有助于治疗诱导的肿瘤侵袭和肿瘤复发和靶向 这些肿瘤周细胞与目前的GBM治疗有协同作用。我们计划测试我们的 通过追求三个特定的目标进行假说：1.确定GSC来源的周细胞在 治疗诱导的癌症侵袭和肿瘤复发。2.明确分子机制 推动GSC来源的周细胞向GSC的去分化。3.确定是否有针对性 GSC来源的周细胞与目前的GBM疗法具有协同作用。我们将使用体内细胞谱系 示踪、选择性靶向和其他新技术来阐明GSC衍生的作用 周细胞在治疗诱导的肿瘤进展中的作用并评估 在临床前环境下，以GSC来源的周细胞为靶点，采用当前的治疗方法。建议数 研究将为开发有效的疗法或新疗法奠定坚实的基础 联合用药可显著提高GBM患者的存活率。

Summary Glioblastoma (GBM) is the most lethal primary brain cancer that is highly invasive and resistant to current treatments. Cancer invasion and tumor recurrence are universal in GBM patients despite maximal therapy. Some treatments such as anti-angiogenic regimens actually transform tumor growth towards a more invasive phenotype. Defining the mechanisms underlying the therapy-induced cancer invasion and tumor repopulation may help improve GBM treatment. GBMs contain abundant vessels consisting of endothelial cells (ECs) and pericytes. Pericytes play critical roles in maintaining vascular function and blood-brain (tumor) barriers. We found that the majority of vascular pericytes in GBMs are derived from glioma stem cells (GSCs), a highly plastic cellular subpopulation functionally defined by self-renewal, multipotency and tumor propagation. Selective targeting of GSC-derived pericytes disrupted tumor vessels and potently inhibited tumor growth, indicating that GSC-derived pericytes play crucial roles in supporting vascular structure and function to promote tumor growth. In addition, GSC-derived pericytes were detected on a subset of vessels in peritumoral brain, suggesting that these neoplastic pericytes have the capacity to migrate into brain tissues. Our recent study using cell lineage tracing demonstrated that GSC-derived pericytes have the potential to de-differentiate into GSCs that are able to grow tumors. Moreover, GSC-derived pericytes are highly resistant to current treatments, indicating that GSC-derived pericytes may function as a reservoir of tumor- initiating cells to promote cancer invasion and tumor recurrence by de-differentiating into GSCs after therapy. Thus, we hypothesize that GSC-derived pericytes are reserve cancer cells that contribute to the therapy-induced cancer invasion and tumor recurrence and targeting these neoplastic pericytes synergizes with current GBM treatments. We plan to test our hypothesis by pursuing three specific aims: 1. Determine roles of GSC-derived pericytes in the therapy-induced cancer invasion and tumor recurrence. 2. Define the molecular mechanisms driving de-differentiation of GSC-derived pericytes into GSCs. 3. Determine whether targeting GSC-derived pericytes synergizes with current GBM therapies. We will use in vivo cell lineage tracing, selective targeting and other new techniques to elucidate the roles of GSC-derived pericytes in the therapy-induced cancer progression and evaluate the synergistic impact of targeting GSC-derived pericytes with current therapies in a preclinical setting. The proposed studies will lay a solid foundation for the development of effective therapeutics or new treatment combinations to significantly improve survival of GBM patients.