Glioblastoma stem cell-derived pericytes and cancer invasion

胶质母细胞瘤干细胞衍生的周细胞和癌症侵袭

• 批准号: 9926320
• 负责人: Shideng Bao
• 金额: $ 34.67万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926320
• 关键词: Automobile Driving; BMX gene; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Lineage; Cells; Data; Development; Drug Delivery Systems; Endothelial Cells; Foundations; Funding; Glioblastoma; Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Molecular; Patients; Pericytes; Phenotype; Play; Radiation; Radiation therapy; Recurrence; Regimen; Resistance; Role; STAT3 gene; Signal Transduction; Solid; Structure; Techniques; Testing; Transforming Growth Factor beta; Treatment Efficacy; blood-brain tumor barrier; brain tissue; cancer cell; improved; in vivo; inhibitor/antagonist; neoplastic; novel therapeutics; pre-clinical; self-renewal; stem cell differentiation; stem cells; temozolomide; tumor; tumor growth; tumor progression

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.

总结 胶质母细胞瘤（GBM）是最致命的原发性脑癌，具有高度侵袭性和耐药性 目前的治疗。肿瘤浸润和复发在GBM患者中是普遍的 尽管进行了最大限度的治疗一些治疗方法，如抗血管生成疗法， 肿瘤向更具侵袭性的表型生长。定义作为基础的机制 治疗诱导的癌症侵袭和肿瘤再增殖可能有助于改善GBM治疗。 GBM含有丰富的血管，由内皮细胞（EC）和周细胞组成。周细胞 在维持血管功能和血脑（肿瘤）屏障中起关键作用。我们发现 GBM中的大多数血管周细胞来源于胶质瘤干细胞（GSC）， 高度可塑性细胞亚群功能定义为自我更新、多能性和肿瘤 传播选择性靶向GSC衍生的周细胞破坏了肿瘤血管， 抑制肿瘤生长，表明GSC衍生的周细胞在支持肿瘤生长中起着至关重要的作用。 血管结构和功能，以促进肿瘤生长。此外，GSC衍生的周细胞 在瘤周脑血管的一个子集上检测到，这表明这些肿瘤性 周细胞具有迁移到脑组织中的能力。我们最近的研究利用细胞谱系 示踪表明，GSC衍生的周细胞具有去分化为 GSC能够生长肿瘤。此外，GSC衍生的周细胞对免疫抑制剂具有高度抗性。 目前的治疗，表明GSC衍生的周细胞可能作为肿瘤的储存库- 通过去分化成GSC来启动细胞以促进癌症侵袭和肿瘤复发 在治疗后。因此，我们假设GSC衍生的周细胞是储备癌细胞， 有助于治疗诱导的癌症侵袭和肿瘤复发以及靶向 这些肿瘤周细胞与目前的GBM治疗协同作用。我们计划测试 通过追求三个具体目标的假设：1。确定GSC衍生的周细胞在 治疗诱导的癌症侵袭和肿瘤复发。2.定义分子机制 驱动GSC衍生的周细胞去分化为GSC。3.确定目标是否 GSC衍生的周细胞与目前的GBM疗法协同作用。我们将使用体内细胞谱系 追踪，选择性靶向和其他新技术，以阐明GSC衍生的作用， 周细胞在治疗诱导的癌症进展中的作用，并评估 在临床前环境中用当前疗法靶向GSC衍生的周细胞。拟议 研究将为开发有效的治疗方法或新的治疗方法奠定坚实的基础。 联合用药可显著提高GBM患者的生存率。