Instructive Cues in Glioblastoma Hierarchies

胶质母细胞瘤层次结构中的指导性线索

• 批准号: 8786649
• 负责人: JEREMY N RICH
• 金额: $ 42.1万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786649
• 关键词: Adopted; Astrocytes; Attenuated; Biological Assay; Bone Morphogenetic Proteins; CDKN1A gene; Cancer Biology; Cell Differentiation process; Cell Maintenance; Cell Survival; Cell Therapy; Cells; Cues; Development; Environment; Epigenetic Process; FDA approved; Gene Expression; Genetic; Glioblastoma; Growth; Human; In Vitro; Injection of therapeutic agent; Interleukin-6; Kidney; Laminin; Lesion; Ligands; Limb structure; Link; Lung; Maintenance; Malignant Neoplasms; Measures; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Normal tissue morphology; Outcome; Pathway interactions; Patients; Pattern; Phenocopy; Phenotype; Population; Primary Brain Neoplasms; Production; Proteins; Regulation; Resistance; Role; Signal Transduction; Specimen; Stem cells; Subgroup; Techniques; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Toxic effect; Transgenic Model; Tumor-Derived; Undifferentiated; Vascular Endothelial Growth Factors; angiogenesis; aptamer; autocrine; base; bevacizumab; bone morphogenic protein; cancer cell; cancer initiation; cancer stem cell; cell growth; conventional therapy; improved; in vivo; inhibitor/antagonist; insight; neoplastic; neoplastic cell; nerve stem cell; notch protein; novel; outcome forecast; palliation; paracrine; prevent; public health relevance; response; self-renewal; skeletal; stem; stem cell niche; tumor; tumor growth; tumor microenvironment; wound

DESCRIPTION (provided by applicant): Glioblastomas are the most common primary brain tumor and the most lethal. Current glioblastoma therapy provides only palliation and these cancers are universally fatal. Although the concept of a tumor cell hierarchy remains controversial, increasing evidence supports the notion that subgroups of stem-like cancer cells contribute to tumor growth. These cancer stem cells stimulate the malignancy of tumor growth through preferential resistance to conventional therapies, stimulation of angiogenesis, and invasion into normal tissues. A central unexplained observation in the cancer stem cell hypothesis is the reestablishment of a cellular hierarchy despite growth advantages of the stem-like cells. Cancer stem cells express pro-differentiation factors, including bone morphogenetic proteins, which may promote the maintenance of differentiated tumor cells that provide signals in support of the cancer stem cells (e.g. Notch ligands, interleukin-6, and laminins). To determine potential microenvironmental interactions that maintain the cellular hierarchy, we interrogated secreted regulators of cellular differentiation that are associated with the cellular hierarchy. We find that glioblastoma stem cells express secreted antagonists of differentiation signals to maintain their growth. Further, forced expression of these molecules in non-stem tumor cells promotes stem-like features. The simultaneous expression of differentiating signals and their inhibitors may create tissue patterning with stem-like and differentiated populations, phenocopying development. As there is an association between expression of anti-differentiation signals and poor glioblastoma patient outcome, we hypothesize that targeting secreted inhibitors of microenvironmental differentiation cues may offer potential therapeutic benefit. The tumor microenvironment provides instructive cues to maintain the cellular hierarchy in both normal and neoplastic tissues; we are therefore developing a set of techniques to interrogate the cellular hierarchy in relevant microenvironments while representing appropriate molecular tumor phenotypes. Overall, this study will examine in vivo response of tumor cells to environmental influences such as bone morphogenic protein antagonists on the self-renewal and maintenance of stem cell-like tumor cells within their niche. Successful execution of this collaborative scientific endeavor promises to bring important new scientific insights into cancer biology, and may have profound implications for glioblastoma treatment paradigms.

描述（由申请人提供）：胶质母细胞瘤是最常见的原发性脑肿瘤，也是最致命的肿瘤。目前的胶质母细胞瘤治疗仅提供姑息治疗，这些癌症普遍是致命的。虽然肿瘤细胞等级的概念仍然存在争议，但越来越多的证据支持干细胞样癌细胞亚群有助于肿瘤生长的观点。这些癌症干细胞通过对常规疗法的优先抗性、刺激血管生成和侵入正常组织来刺激肿瘤生长的恶性性。癌症干细胞假说中一个无法解释的核心观察结果是，尽管干细胞样细胞具有生长优势，但细胞层次结构的重建。癌症干细胞表达促分化因子，包括骨形态发生蛋白，其可促进提供支持癌症干细胞的信号的分化肿瘤细胞的维持（例如Notch配体、白细胞介素-6和层粘连蛋白）。为了确定维持细胞层次的潜在微环境相互作用，我们询问了与细胞层次相关的细胞分化的分泌调节因子。我们发现，胶质母细胞瘤干细胞表达分化信号的分泌拮抗剂，以维持其生长。此外，这些分子在非干细胞肿瘤细胞中的强制表达促进了干细胞样特征。分化信号及其抑制剂的同时表达可以产生具有干细胞样和分化群体的组织模式，表型复制发育。由于抗分化信号的表达与胶质母细胞瘤患者预后不良之间存在相关性，我们假设靶向微环境分化线索的分泌抑制剂可能提供潜在的治疗益处。肿瘤微环境提供了有益的线索，以维持正常和肿瘤组织中的细胞层次结构;因此，我们正在开发一套技术来询问相关微环境中的细胞层次结构，同时代表适当的分子肿瘤表型。总体而言，本研究将检查肿瘤细胞对环境影响的体内反应，例如骨形态发生蛋白拮抗剂对干细胞样肿瘤细胞在其小生境内的自我更新和维持的影响。这种合作科学奋进的成功执行有望为癌症生物学带来重要的新科学见解，并可能对胶质母细胞瘤治疗模式产生深远的影响。