Stem Cell-Like Glioma Cells in Angiogenesis

描述(申请人提供)：胶质母细胞瘤是一种高度致命的癌症，传统治疗基本上是姑息治疗。我们最近证明了胶质母细胞瘤细胞的一个子集，即肿瘤干细胞，具有与体神经干细胞相同的特征，对辐射具有抵抗力，并具有高度的血管生成能力。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整体行为的重要决定因素，癌症干细胞定向治疗可能在控制胶质母细胞瘤生长方面有效。抗血管生成疗法可能作为抗干细胞疗法发挥作用，不仅通过破坏肿瘤干细胞的血管生成，而且还可能破坏促进肿瘤干细胞维持的血管生态位。这种方法具有直接的治疗意义，因为Bevacizumab(阿瓦斯丁)，一种血管内皮生长因子中和抗体，已经在胶质母细胞瘤患者的临床试验中显示出活性，支持脑瘤的抗血管生成治疗的潜在用途。抗癌干细胞方法成功的关键是限制对正常干细胞的毒性。肿瘤细胞处于相对低氧状态，这与肿瘤血管生成、侵袭和耐药有关。低氧可增加干细胞的维持，提示低氧对肿瘤干细胞的影响可能与肿瘤的恶性有关。为了研究肿瘤血管在肿瘤干细胞生物学中的作用，并为潜在的新的治疗方法奠定基础，我们提出：1)检测肿瘤干细胞在生存、血管生成因子分泌和侵袭过程中对低氧的反应。2)确定与正常神经干细胞相比，驱动肿瘤干细胞对缺氧的特异性反应的分子机制。3)确定癌症干细胞是否为患者对贝伐单抗治疗的反应提供了生物标志物。这些研究的成功完成将更好地确定肿瘤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)确定靶向肿瘤干细胞缺氧反应是否使肿瘤对细胞毒治疗(放疗、化疗)敏感。公共卫生相关性：癌症干细胞假说可能为胶质母细胞瘤血管生成和辐射抵抗提供新的见解。我们现在试图在我们之前对胶质母细胞瘤干细胞的研究的基础上，了解这些细胞在放疗和化疗后显示出优先的血管生成和存活的机制。这些研究可能允许选择性靶向癌症干细胞，以提高肿瘤对治疗的反应。

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELAVANCE: 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.