Biochemistry of Brain Tumor Microvessel Development

脑肿瘤微血管发育的生物化学

• 批准号: 7265156
• 负责人: John J Laterra
• 金额: $ 36.26万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265156
• 关键词: 1-Phosphatidylinositol 3-Kinase; Biochemical; Biochemistry; Biological; Biological Models; Blood - brain barrier anatomy; Brain Neoplasms; Candidate Disease Gene; Cell Cycle; Cell Cycle Progression; Cell Line; Cells; Clinical; Cytotoxic Chemotherapy; Data; Development; Event; Functional disorder; Funding; Gene Expression; Gene Family; Genes; Glioblastoma; Glioma; Growth Factor; Hepatocyte Growth Factor; Human; In Vitro; Investigation; Lesion; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Mediating; Microarray Analysis; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Target; Oncogenic; Operative Surgical Procedures; Pathway interactions; Phenotype; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Principal Investigator; Proliferative Index; Property; Proteins; Radio; Rattus; Receptor Protein-Tyrosine Kinases; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Second Messenger Systems; Signal Pathway; Signal Transduction; Specimen; Study models; Therapeutic; Tissue Microarray; Tumor Angiogenesis; Xenograft procedure; angiogenesis; autocrine; base; cell motility; cytokine; cytotoxic; gain of function; in vivo; interest; loss of function; malignant phenotype; migration; novel; novel therapeutics; paracrine; programs; receptor; research study; response; second messenger; therapeutic target; transcription factor; tumor

DESCRIPTION (provided by applicant): Gliomas remain among the least curable of human tumors despite the most aggressive surgical, radio- and chemo-therapeutics. The identification of molecular pathways that contribute to glioma malignancy is vital to the development of more effective therapeutics. We and others established that expression of the multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-Met in human gliomas significantly correlates with degree of malignancy. During the last funding period, we combined gain-of-function and loss-of-function approaches with in vivo and in vitro glioma model systems to establish that SF/HGF:c-Met signaling activates autocrine and paracrine events that stimulate glioma malignancy (i.e. tumor angiogenesis, blood-brain barrier dysfunction, glioma cell cycle dysregulation and cell migration, chemo/radioresistance). We have partially characterized the mechanisms by which gliomas respond to SF/HGF:c-Met signal activation. This competing renewal proposes to utilize experimental glioma models and clinical tumor specimens to further identify biochemical and transcriptional mechanisms by which SF/HGF stimulates the malignant phenotype in human gliomas. Aim #1 will identify novel genes and gene families that are differentially regulated by SF/HGF:c-Met activation in human glioblastoma cells. Aim #2 will utilize novel hypotheses generated in aim #1 to determine how specific SF/HGF-regulated genes contribute to the malignant glioma phenotype. Aim #3 will identify cell signaling pathways and transcriptional mechanisms by which glioma cells respond to SF/HGF. Aim #4 will use tissue arrays to quantify expression of the biologically-important SF/HGF-responsive genes in clinical human gliomas and determine their correlation with pathological grade and other features of malignancy. The successful completion of the proposed experiments will reveal novel mechanisms of growth factor-stimulated glioma malignancy and new therapeutic targets for clinical development.

描述（由申请人提供）：胶质瘤仍然是最难治愈的人类肿瘤之一，尽管最积极的手术，放射和化学治疗。鉴定导致胶质瘤恶性的分子通路对于开发更有效的治疗方法至关重要。我们和其他人建立了多功能生长因子分散因子/肝细胞生长因子（SF/HGF）及其酪氨酸激酶受体c-Met在人脑胶质瘤中的表达与恶性程度显著相关。在最后一个资助期间，我们将功能获得和功能丧失方法与体内和体外胶质瘤模型系统相结合，以确定SF/HGF：c-Met信号转导激活刺激胶质瘤恶性的自分泌和旁分泌事件（即肿瘤血管生成、血脑屏障功能障碍、胶质瘤细胞周期失调和细胞迁移、化疗/放射抗性）。我们已经部分表征了神经胶质瘤对SF/HGF：c-Met信号激活的反应机制。 这种竞争性的更新建议利用实验性胶质瘤模型和临床肿瘤标本，以进一步确定SF/HGF刺激人类胶质瘤恶性表型的生化和转录机制。目的#1将鉴定在人胶质母细胞瘤细胞中由SF/HGF：c-Met活化差异调节的新基因和基因家族。目标#2将利用目标#1中产生的新假设来确定特定SF/HGF调节基因如何促成恶性胶质瘤表型。目的#3将确定神经胶质瘤细胞对SF/HGF应答的细胞信号传导途径和转录机制。目的#4将使用组织阵列来量化临床人类胶质瘤中生物学上重要的SF/HGF应答基因的表达，并确定其与病理学分级和恶性肿瘤的其他特征的相关性。该实验的成功完成将为进一步揭示生长因子刺激胶质瘤恶性化的新机制和临床开发新的治疗靶点奠定基础。

项目成果

Scatter factor/hepatocyte growth factor stimulation of glioblastoma cell cycle progression through G(1) is c-Myc dependent and independent of p27 suppression, Cdk2 activation, or E2F1-dependent transcription.

分散因子/肝细胞生长因子通过 G(1) 对胶质母细胞瘤细胞周期进展的刺激是 c-Myc 依赖性的，并且独立于 p27 抑制、Cdk2 激活或 E2F1 依赖性转录。

• DOI: 10.1128/mcb.22.8.2703-2715.2002
• 发表时间: 2002
• 期刊: Molecular and cellular biology
• 影响因子: 5.3
• 作者: Walter,KevinA;Hossain,MirAhamed;Luddy,Carey;Goel,Nidhi;Reznik,ThomasE;Laterra,John
• 通讯作者: Laterra,John

Regulation of angiogenesis in malignant gliomas.

恶性神经胶质瘤中血管生成的调节。

• DOI: 10.1007/978-3-0348-9006-9_4
• 发表时间: 1997
• 期刊: EXS.
• 作者: Guerin,C;Laterra,J
• 通讯作者: Laterra,J

Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp.

• DOI: 10.1593/neo.81264
• 发表时间: 2009
• 期刊: Neoplasia
• 影响因子: 4.8
• 作者: Yimao Zhang;J. Laterra;M. Pomper

Design and expression of chimeric U1/ribozyme transgenes.

嵌合 U1/核酶转基因的设计和表达。

• DOI: 10.1385/1-59259-746-7:209
• 发表时间: 2004
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Abounader,Roger;Montgomery,Robert;Dietz,Harry;Laterra,John
• 通讯作者: Laterra,John

Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways.

• 发表时间: 2000-08
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Daniel C. Bowers;Saijun Fan;Kevin A. Walter;R. Abounader;Jeffery A. Williams;E. Rosen;J. Laterra