The effects of the unfolded protein response on medulloblastoma

未折叠蛋白反应对髓母细胞瘤的影响

• 批准号: 8712569
• 负责人: Wensheng Lin
• 金额: $ 32.92万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712569
• 关键词: Affect; Age-Months; Autophagocytosis; Biological Assay; Cell Culture Techniques; Cells; Cerebellar Neoplasms; Cerebellum; Child; Childhood; Childhood Malignant Brain Tumor; Complex; DNA Damage; Data; Development; Disease; Dysplasia; Embryonal Neoplasms; Endoplasmic Reticulum; Erinaceidae; Genes; Genetic; Goals; Growth; Human; Hypoxia; In Vitro; Incidence; Interferons; Invaded; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Malnutrition; Mediating; Molecular Target; Mus; Mutant Strains Mice; Mutation; Neuraxis; Pancreas; Pathway interactions; Patients; Peptide Initiation Factors; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Prokaryotic Initiation Factor-2; Protein Biosynthesis; Proteins; Resistance; Role; Signal Pathway; Signal Transduction; Solid; Sonic Hedgehog Pathway; Stress; Survival Rate; Testing; Therapeutic Intervention; Tissue Sample; Transgenic Mice; Tumor Cell Invasion; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Work; Wound Healing; Xenograft Model; angiogenesis; autocrine; biological adaptation to stress; cell motility; chemotherapeutic agent; chemotherapy; design; expectation; insight; matrigel; medulloblastoma; neoplastic cell; novel; novel therapeutics; programs; protein misfolding; receptor; response; smoothened signaling pathway; sonic hedgehog receptor; tumor; tumor growth; tumor microenvironment; tumor progression; tumor xenograft; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is a highly malignant pediatric brain tumor with a 5-year survival rate of ~ 60%. Multiple signaling pathways, such as the sonic hedgehog (SHH) pathway, have been associated with MB tumorigenesis. Nevertheless, little is known about the mechanisms that regulate MB invasion and angiogenesis. Evidence is emerging that the unfolded protein response (UPR) activated in response to the tumor microenvironment plays a role in tumor development. Activation of the pancreatic endoplasmic reticulum kinase (PERK) branch of the UPR inhibits global protein biosynthesis, but stimulates the expression of certain stress-induced genes, such as vascular endothelial growth factor A (VEGF), by phosphorylating translation initiation factor 21 (eIF21). Data indicate that tumor cell-derived VEGF not only enhances angiogenesis but also acts directly on tumor cells in an autocrine manner to promote tumor growth and invasion. Interestingly, a recent study suggested a possible autocrine role of VEGF in MB growth. Our previous studies showed that enforced expression of interferon-3 in the central nervous system during development led to cerebellar dysplasia or MB. Importantly, our preliminary data suggested that activation of the PERK-eIF21 pathway facilitated interferon-3-induced MB formation. Thus, in this proposal, we will test the hypothesis that the PERK branch of the UPR promotes MB development by enhancing the tumor cell invasion and angiogenesis through the induction of VEGF, and renders MB cells resistant to chemotherapy. In the first specific aim, we will manipulate the activity of the PERK-eIF21 pathway using genetic approaches to determine whether the UPR influences MB formation in mice with heterozygous deficiency of patched1, a SHH receptor. We will also assess the effects of the PERK-eIF21 pathway on angiogenesis, tumor cell invasion and proliferation, and the expression of VEGF in the tumors. In the second specific aim, we will determine whether activation of the PERK-eIF21 pathway promotes MB cell migration and invasion through the induction of VEGF utilizing in vitro cell cultures. Moreover, we will determine whether the pro-tumorigenesis actions of PERK signaling are mediated by autocrine VEGF/VEGF receptor 2 signaling in MB cells utilizing an intracerebellar MB xenograft model. In the final specific aim, we will determine whether the UPR is activated in MB in human patients. Additionally, we will explore the role of the PERK-eIF21 pathway in MB resistance to chemotherapy and its underlying mechanisms. The significance of this proposed work is that it will uncover a novel mechanism responsible for MB invasion, angiogenesis, and chemotherapy resistance. The knowledge gained from these studies will have important implications for MB tumorigenesis and may lead to novel therapeutic strategies for treating this disease.

描述（由申请人提供）：髓母细胞瘤（MB）是一种高度恶性的儿科脑肿瘤，5年生存率约为60%。多种信号传导途径，如音刺猬（SHH）途径，已与MB肿瘤发生。然而，很少有人知道的机制，调节MB入侵和血管生成。有证据表明，在肿瘤微环境中激活的未折叠蛋白反应（UPR）在肿瘤发生中起作用。UPR的胰腺内质网激酶（PERK）分支的激活抑制整体蛋白质生物合成，但通过磷酸化翻译起始因子21（eIF 21）刺激某些应激诱导的基因（例如血管内皮生长因子A（VEGF））的表达。有资料表明，肿瘤细胞来源的VEGF不仅能增强血管生成，而且能以自分泌方式直接作用于肿瘤细胞，促进肿瘤生长和侵袭。有趣的是，最近的一项研究表明，MB生长中VEGF可能具有自分泌作用。我们以前的研究表明，在发育过程中，干扰素-3在中枢神经系统中的强制表达导致小脑发育不良或MB。重要的是，我们的初步数据表明，PERK-eIF 21通路的激活促进干扰素-3诱导的MB形成。因此，在本提案中，我们将检验UPR的PERK分支通过诱导VEGF增强肿瘤细胞侵袭和血管生成来促进MB发展，并使MB细胞对化疗具有抗性的假设。在第一个具体目标中，我们将使用遗传方法操纵PERK-eIF 21通路的活性，以确定UPR是否影响具有杂合缺陷patched 1（SHH受体）的小鼠的MB形成。我们还将评估PERK-eIF 21通路对血管生成、肿瘤细胞侵袭和增殖以及肿瘤中VEGF表达的影响。在第二个具体目标中，我们将确定PERK-eIF 21途径的激活是否通过利用体外细胞培养物诱导VEGF来促进MB细胞迁移和侵袭。此外，我们将利用小脑内MB异种移植模型确定PERK信号传导的促肿瘤发生作用是否由MB细胞中的自分泌VEGF/VEGF受体2信号传导介导。在最终的具体目标中，我们将确定UPR是否在人类患者的MB中被激活。此外，我们将探讨PERK-eIF 21通路在MB耐化疗及其潜在机制中的作用。这项工作的意义在于它将揭示一种新的机制，负责MB的入侵，血管生成和化疗耐药性。从这些研究中获得的知识将对MB肿瘤发生产生重要影响，并可能导致治疗这种疾病的新的治疗策略。