Stem Cell-Like Glioma Cells in Angiogenesis

胶质母细胞瘤是一种高度致命的癌症，传统的治疗方法基本上是无法治愈的。 治标不治本。我们最近证明了一组胶质母细胞瘤细胞共享 体细胞神经干细胞的特性，癌症干细胞，是抵抗辐射和 血管生成能力很强。结合其他实验室的数据，我们的结果表明 肿瘤干细胞是胶质母细胞瘤整体行为的重要决定因素， 肿瘤干细胞导向治疗可能在控制胶质母细胞瘤生长方面有效。反- 血管生成疗法可能作为抗干细胞疗法发挥作用，不仅仅是通过破坏 肿瘤干细胞血管生成，但也可能破坏促进肿瘤干细胞的血管壁龛 牢房维护。这种方法与贝伐单抗(阿瓦斯丁)有直接的治疗相关性， 血管内皮生长因子中和抗体在胶质母细胞瘤患者的临床试验中显示出活性 支持脑肿瘤抗血管生成治疗的潜在效用。对成功至关重要 抗癌干细胞方法的关键是限制对正常干细胞的毒性。癌 细胞处于相对低氧状态，这与肿瘤血管生成、侵袭和 对治疗的抗拒。缺氧增加了干细胞的维持，这表明 肿瘤干细胞上的低氧可能与肿瘤的恶性程度有关。调查……的作用 肿瘤血管构筑在肿瘤干细胞生物学中的应用并为潜在的新的 治疗方法，我们建议：1)询问癌症干细胞对 缺氧在生存、血管生成因子的分泌和侵袭中起重要作用。2)确定分子 与正常神经相比，驱动肿瘤干细胞对缺氧的特异性反应的机制 干细胞。3)确定癌症干细胞是否为患者治疗反应提供了生物标志物 贝伐单抗疗法。这些研究的成功完成将更好地界定 肿瘤干细胞在胶质母细胞瘤生物学研究中提供直接的治疗益处。4)确定是否 靶向肿瘤干细胞缺氧反应使肿瘤对细胞毒治疗敏感 (放射治疗、化疗)。项目叙事 肿瘤干细胞假说可能为胶质母细胞瘤的血管生成和辐射提供新的见解 抵抗。我们现在寻求建立在我们之前对胶质母细胞瘤干细胞的研究基础上，以了解 这些细胞在放射治疗中表现出优先血管生成和存活的机制 还有化疗。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。

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.