Paracrine Signaling in Glioma: Bioenergetics Heterogeneity and Chemoresistance

神经胶质瘤中的旁分泌信号传导：生物能异质性和化疗耐药性

• 批准号: 9221192
• 负责人: Corinne E. Griguer
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221192
• 关键词: Attention; Binding Proteins; Bioenergetics; Biomass; Cells; Cellular Metabolic Process; Characteristics; Connective Tissue; Development; Diagnosis; Dose; Foundations; Genetic; Glioma; Glycolysis; Goals; Grant; Growth; Growth Factor Gene; Heterogeneity; Human; Human Cell Line; IGF2 gene; Individual; Insulin; Insulin-Like Growth-Factor-Binding Proteins; Malignant Neoplasms; Mitochondria; Modality; Modeling; Nutrient; Outcome; Oxidases; Oxidative Phosphorylation; Oxygen; Paracrine Communication; Pathway interactions; Patients; Phenotype; Population; Protein Isoforms; Recurrence; Regulation; Role; Signal Pathway; Signal Transduction; Source; Structure; System; Testing; Tumorigenicity; United States National Institutes of Health; Warburg Effect; Work; cancer cell; cell type; cytochrome c oxidase; density; design; effective therapy; killings; neoplastic cell; new therapeutic target; novel; paracrine; standard care; standard of care; temozolomide; tumor; tumor growth; tumor heterogeneity; tumor progression

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. Much attention has been placed on tumors as architecturally heterogeneous systems that differ regionally in vasculature, host infiltrates, and connective tissue components, but far less is known about bioenergetic heterogeneity and how cancer cells dependent on different bioenergetic pathways interact together to drive tumor growth. In this application, we propose to test the hypothesis that glycolytic chemosensitive glioma cells inhibit the expansion and growth of Oxphos-dependent chemoresistant glioma cells through a paracrine mechanism involving secreted insulin growth factor binding protein 6 (IGFBP6). Two aims are proposed to: 1) Characterize the paracrine pathway between glycolytic chemosensitive cells and Oxphos- dependent chemoresistant cells, and 2) Determine the effect of TMZ treatment on the enrichment of Oxphos-dependent chemoresistant cells. In both aims, we will use genetic and pharmacologic approaches in human cell lines and patient–derived xenoline models. The work proposed is expected to identify a novel paracrine pathway between Oxphos-dependent chemoresistant and glycolytic chemosensitive glioma cells and demonstrate that standard of care TMZ, by interrupting this paracrine regulation, expands the pool of chemoresistant cells, leading to increased tumorigenicity. If successful, this study will define a novel tumor growth model where by intratumoral bioenergetic heterogeneity is critically involved in the growth of the tumor as a whole. Importantly, we propose that standard treatment modalities may selectively destroy this structured population and facilitate subsequent progression. Consequently, controlling tumor progression by maintaining rather than destroying this suppressive tumor layer may be more effective than conventional high-dose density therapy that aims to kill the maximum possible number of tumor cells.

异质性是肿瘤的一个标志，对恶性肿瘤的结局起着至关重要的作用， 因为它不仅混淆了诊断，还挑战了有效疗法的设计。 肿瘤作为一种不同结构的异质系统，受到了人们的广泛关注。 在血管系统、宿主浸润物和结缔组织成分方面，但远远少于 已知生物能量异质性以及癌细胞如何依赖于不同的 生物能量途径相互作用，推动肿瘤生长。在本申请中，我们建议 验证糖酵解药物敏感的胶质瘤细胞抑制其增殖和生长的假说 OXPHOS依赖的耐药神经胶质瘤细胞的旁分泌机制 分泌胰岛素生长因子结合蛋白6(IGFBP6)。提出了两个目标：1) 糖酵解化疗敏感细胞与OXPHOS之间旁分泌途径的特征 依赖化疗耐药细胞，以及2)确定TMZ治疗对细胞的影响。 OXPHOS依赖的化疗耐药细胞的浓缩。在这两个目标中，我们将使用遗传和 人类细胞系和患者来源的磷脂模型的药理学方法。这项工作 有望发现一种新的旁分泌途径，在依赖OXPHOS的 化疗耐药和糖酵解化疗敏感的胶质瘤细胞，并证明了 CARE TMZ通过中断这种旁分泌调节，扩大了化疗耐药细胞池， 导致肿瘤致瘤性增加。如果成功，这项研究将定义一种新的肿瘤生长 肿瘤内生物能量的异质性在肿瘤的生长中起关键作用的模型 肿瘤作为一个整体。重要的是，我们建议标准的治疗方式可以选择性地 摧毁这种有结构的人口，并促进随后的进步。因此， 通过维持而不是破坏这种抑制性肿瘤层来控制肿瘤进展 可能比传统的高剂量密度疗法更有效，旨在杀死 肿瘤细胞的最大可能数量。