Stem Cell-Like Glioma Cells in Angiogenesis

血管生成中的干细胞样神经胶质瘤细胞

• 批准号: 8208010
• 负责人: JEREMY N RICH
• 金额: $ 31.6万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-07 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208010
• 关键词: Angiogenic Factor; Animal Model; Animals; Attenuated; Automobile Driving; Avastin; Behavior; Biological; Biological Markers; Biology; Biopsy Specimen; Blood Vessels; Brain Neoplasms; Cell Fraction; Cell Maintenance; Cell Survival; Cells; Characteristics; Clinical; Clinical Trials; Cytotoxic Chemotherapy; DNA damage checkpoint; Data; Development; Endothelial Cells; Foundations; Genes; Genetic Transcription; Glioblastoma; Glioma; Growth; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Laboratories; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Operative Surgical Procedures; Outcome; Patients; Phase II Clinical Trials; Platelet Factor 4; Proteins; RNA Interference; Radiation; Radiation therapy; Recurrence; Relative (related person); Reporting; Resistance; Role; Specimen; Stem cells; Therapeutic; Toxic effect; Tumor Angiogenesis; Tumor Vascular Invasion; Vascular Endothelial Growth Factors; Work; Xenograft procedure; angiogenesis; antiangiogenesis therapy; bevacizumab; c-myc Genes; cancer cell; cancer stem cell; cell behavior; chemotherapy; conventional therapy; design; hypoxia inducible factor 1; improved; in vivo; insight; irinotecan; method development; nerve stem cell; neutralizing antibody; novel; novel therapeutic intervention; palliative; protein expression; radiation resistance; research study; response; self-renewal; stem; stem cell biology; stem cell therapy; success; therapy resistant; transcription factor; tumor; tumor growth; tumorigenesis; tumorigenic

Glioblastomas are highly lethal cancers for which conventional therapies are essentially palliative. We recently demonstrated that a subset of glioblastoma cells that share characteristics with somatic neural stem cells, cancer stem cells, are resistant to radiation and highly angiogenic. In combination with data from other laboratories, our results suggest that cancer stem cells are important determinants of the overall behavior of glioblastomas and that cancer stem cell directed therapies may be effective in controlling glioblastoma growth. Anti- angiogenic therapies may function as anti-stem cell therapies not only through the disruption of cancer stem cell angiogenesis but may also disrupt the vascular niche promoting cancer stem cell maintenance. This approach has direct therapeutic relevance as Bevacizumab (Avastin), a VEGF neutralizing antibody, has demonstrated activity in clinical trials for glioblastoma patients supporting potential utility of anti-angiogenic therapies for brain tumors. Critical to the success of anti-cancer stem cell approaches will be the limitation of toxicity to normal stem cells. Cancer cells reside in relative hypoxia, which has been linked to tumor angiogenesis, invasion, and resistance to therapy. Hypoxia increases stem cell maintenance suggesting that effects of hypoxia on cancer stem cells may contribute to tumor malignancy. To investigate the role of tumor vasculature in cancer stem cell biology and lay the foundation for potential new therapeutic approaches, we propose to: 1) Interrogate the response of cancer stem cells to hypoxia in survival, secretion of angiogenic factors, and invasion. 2) Determine the molecular mechanisms driving cancer stem cell specific responses to hypoxia relative to normal neural stem cells. 3) Determine if cancer stem cells provide a biomarker for patient response to bevacizumab therapy. The successful completion of these studies will better define the role of cancer stem cells in glioblastoma biology and provide direct therapeutic benefit. 4) Determine if targeting cancer stem cell hypoxic responses sensitizes tumors to cytotoxic therapies (radiotherapy, chemotherapy). PROJECT NARRATIVE The cancer stem cell hypothesis may offer novel insights into glioblastoma angiogenesis and radiation resistance. We now seek to build on our prior studies of glioblastoma stem cells to understand the mechanisms by which these cells display preferential angiogenesis and survival upon treatment with radiation and chemotherapy. These studies may permit the selective targeting of cancer stem cells to improve tumor response to therapy.

胶质母细胞瘤是高度致命的癌症，常规治疗基本上是 姑息治疗我们最近证明了一个胶质母细胞瘤细胞亚群， 体细胞神经干细胞，癌症干细胞的特性，是耐辐射的， 高度血管生成。结合其他实验室的数据，我们的结果表明， 癌症干细胞是胶质母细胞瘤总体行为的重要决定因素， 针对癌症干细胞的治疗可有效控制胶质母细胞瘤生长。反 血管生成疗法可作为抗干细胞疗法发挥作用， 癌症干细胞血管生成，但也可能破坏血管生态位， 细胞维护这种方法具有直接的治疗相关性，因为贝伐单抗（阿瓦斯丁）， VEGF中和抗体，已在胶质母细胞瘤患者的临床试验中显示出活性 支持抗血管生成疗法对脑肿瘤的潜在效用。成功的关键 抗癌干细胞方法的最大缺点将是对正常干细胞的毒性限制。癌 细胞处于相对缺氧状态，这与肿瘤血管生成、侵袭和 对治疗的抵抗缺氧增加了干细胞的维持，这表明 肿瘤干细胞缺氧可能导致肿瘤恶性化。调查的作用 肿瘤干细胞生物学中的肿瘤脉管系统，并为潜在的新的 治疗方法，我们建议：1）询问癌症干细胞对 缺氧存活、血管生成因子的分泌和侵袭。2)测定分子 与正常神经细胞相比，癌症干细胞对缺氧的特异性反应的驱动机制 干细胞3)确定癌症干细胞是否为患者对以下疾病的反应提供生物标志物： 贝伐单抗治疗。这些研究的成功完成将更好地确定 癌症干细胞在胶质母细胞瘤生物学中的作用，并提供直接的治疗益处。4)确定是否 靶向癌症干细胞缺氧反应使肿瘤对细胞毒性疗法敏感 （放射疗法、化学疗法）。项目叙述 癌症干细胞假说可能为胶质母细胞瘤血管生成和辐射提供新的见解 阻力我们现在寻求建立在我们先前对胶质母细胞瘤干细胞的研究的基础上，以了解胶质母细胞瘤干细胞的作用。 这些细胞在放射治疗后表现出优先血管生成和存活的机制 和化疗。这些研究可能允许选择性靶向癌症干细胞，以改善肿瘤 对治疗的反应。

项目成果

Mitotic control of cancer stem cells.

• DOI: 10.1158/2159-8290.cd-12-0588
• 发表时间: 2013-02
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Venere M;Miller TE;Rich JN
• 通讯作者: Rich JN

The evolving landscape of glioblastoma stem cells.

胶质母细胞瘤干细胞不断发展的景观。

• DOI: 10.1097/wco.0000000000000032
• 发表时间: 2013-12
• 期刊: Current opinion in neurology
• 影响因子: 4.8
• 作者: Yan K;Yang K;Rich JN
• 通讯作者: Rich JN

Glioma stem cell maintenance: the role of the microenvironment.

• DOI: 10.2174/138161211797249260
• 发表时间: 2011
• 期刊: Current pharmaceutical design
• 影响因子: 3.1
• 作者: Heddleston JM;Hitomi M;Venere M;Flavahan WA;Yang K;Kim Y;Minhas S;Rich JN;Hjelmeland AB
• 通讯作者: Hjelmeland AB

Acquisition of meiotic DNA repair regulators maintain genome stability in glioblastoma.

• DOI: 10.1038/cddis.2015.75
• 发表时间: 2015-04-23
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Rivera M;Wu Q;Hamerlik P;Hjelmeland AB;Bao S;Rich JN
• 通讯作者: Rich JN

Deadly teamwork: neural cancer stem cells and the tumor microenvironment.

• DOI: 10.1016/j.stem.2011.04.013
• 发表时间: 2011-05-06
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Lathia, Justin D.;Heddleston, John M.;Venere, Monica;Rich, Jeremy N.
• 通讯作者: Rich, Jeremy N.