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: 8234614
• 负责人: Wensheng Lin
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234614
• 关键词: Affect; Age-Months; Autophagocytosis; Biological Assay; Cell Culture Techniques; Cells; Cerebellar Neoplasms; Cerebellum; Child; Childhood; Childhood Brain Neoplasm; 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 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. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common malignant brain tumor in children. The goal of this project is to understand the role of the unfolded protein response in medulloblastoma development and chemotherapy resistance. This will provide novel insights into how medulloblastoma cells acquire the abilities to invade and promote angiogenesis and help identify new molecular targets for therapeutic intervention in patients with this disease.

描述（申请人提供）：髓母细胞瘤（Medulloblastoma， MB）是一种高度恶性的小儿脑肿瘤，5年生存率约为60%。多种信号通路，如sonic hedgehog （SHH）通路，与MB肿瘤发生有关。然而，对MB侵袭和血管生成的调控机制知之甚少。越来越多的证据表明，肿瘤微环境激活的未折叠蛋白反应（UPR）在肿瘤发展中起着重要作用。UPR的胰内质网激酶（PERK）分支的激活抑制了整体蛋白质的生物合成，但通过磷酸化翻译起始因子21 （eIF21）刺激了某些应激诱导基因的表达，如血管内皮生长因子A （VEGF）。数据表明，肿瘤细胞源性VEGF不仅能促进血管生成，还能以自分泌的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VEGF可能在MB生长中起自分泌作用。我们之前的研究表明，在发育过程中中枢神经系统中干扰素-3的强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，激活PERK-eIF21通路促进了干扰素-3诱导的MB形成。因此，在本提案中，我们将验证UPR的PERK分支通过诱导VEGF增强肿瘤细胞的侵袭和血管生成来促进MB的发展，并使MB细胞对化疗产生耐药性的假设。在第一个特定目标中，我们将使用遗传学方法操纵PERK-eIF21通路的活性，以确定UPR是否影响SHH受体patche1杂合缺陷小鼠的MB形成。我们还将评估PERK-eIF21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。在第二个特定目标中，我们将利用体外细胞培养来确定PERK-eIF21通路的激活是否通过诱导VEGF来促进MB细胞的迁移和侵袭。此外，我们将利用小脑内MB异种移植模型来确定PERK信号的促肿瘤作用是否由MB细胞中自分泌的VEGF/VEGF受体2信号介导。在最后的具体目标中，我们将确定UPR是否在人类MB患者中被激活。此外，我们将探讨PERK-eIF21通路在MB化疗耐药中的作用及其潜在机制。这项工作的意义在于，它将揭示MB侵袭、血管生成和化疗耐药的新机制。从这些研究中获得的知识将对MB肿瘤发生具有重要意义，并可能导致治疗这种疾病的新治疗策略。