高压氧治疗胶质瘤的另一个证据

低氧微环境保证了胶质母细胞瘤干细胞的生存并促进了细胞向肿瘤干细胞显型的发展。

题目很长，意义只有一个：缺氧环境导致了胶质瘤对治疗的抵制，促进了肿瘤的存在和生长。因为高压氧能改变这种缺氧环境，所以完全可以抑制胶质瘤生长。上海东方医院神经外科魏社鹏

行动吧，去做高压氧！！！ 

Cell Cycle. 2009 Oct 3;8(20)

The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype

Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN.

Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA.

Glioblastomas are highly lethal cancers that contain cellular hierarchies with self-renewing cancer stem cells that can propagate tumors in secondary transplant assays. The potential significance of cancer stem cells in cancer biology has been demonstrated by studies showing contributions to therapeutic resistance, angiogenesis and tumor dispersal. We recently reported that physiologic oxygen levels differentially induce hypoxia inducible factor-2alpha (HIF2alpha) levels in cancer stem cells. HIF1alpha functioned in proliferation and survival of all cancer cells but also was activated in normal neural progenitors suggesting a potentially restricted therapeutic index while HIF2alpha was essential in only in cancer stem cells and was not expressed by normal neural progenitors demonstrating HIF2alpha is a cancer stem cell specific target. We now extend these studies to examine the role of hypoxia in regulating tumor cell plasticity. We find that hypoxia promotes the self-renewal capability of the stem and non-stem population as well as promoting a more stem-like phenotype in the non-stem population with increased neurosphere formation as well as upregulation of important stem cell factors, such as OCT4, NANOG and c-MYC. The importance of HIF2alpha was further supported as forced expression of non-degradable HIF2alpha induced a cancer stem cell marker and augmented the tumorigenic potential of the non-stem population. This novel finding may indicate a specific role of HIF2alpha in promoting glioma tumorigenesis. The unexpected plasticity of the nonstem glioma population and the stem-like phenotype emphasizes the importance of developing therapeutic strategies targeting the microenvironmental influence on the tumor in addition to cancer stem cells.

胶质母细胞瘤是一种高度致命性的肿瘤。瘤细胞种类各异，其中含有能自我更新的肿瘤干细胞，这种细胞能在新的移植个体中继续增殖演变为肿瘤。在肿瘤生物学中，肿瘤干细胞潜在意义不仅它能抵制治疗，还在于它能诱导新生血管形成和肿瘤播散。最近研究者发现生理条件下不同的氧气水平能影响肿瘤干细胞中低氧诱导因子2α(HIF2alpha) 的水平。低氧诱导因子2α能诱导肿瘤细胞增殖，帮助肿瘤细胞存活。低氧诱导因子2α在正常的神经始祖细胞中被激活，暗示出了一种潜在受限的治疗指数。低氧诱导因子2α仅仅在肿瘤干细胞中是必要的，但在正常神经始祖细胞中并不被表达，显示出低氧诱导因子2α是肿瘤干细胞的特定靶点。

我们现在将这种研究扩展到了低氧在调节肿瘤细胞可塑性方面。我们发现低氧促进了干细胞和非干细胞群的自我更新能力，并促进了非干细胞群体中一种干细胞类似表型的出现，导致了神经球的形成以及重要的干细胞因子的上调，例如OCT4, NANOG 和 c-MYC。低氧诱导因子2α的重要性还在于  非降解的低氧诱导因子2α的强力表达诱导了肿瘤干细胞标记，增加了非干细胞群体的肿瘤原性。这种新的发现可能会表明低氧诱导因子2α在促进胶质瘤肿瘤原性的特定的作用。非干细胞胶质瘤细胞群的不可预料的可塑性以及干细胞类似的细胞群共同强调了发展针对肿瘤细胞和肿瘤干细胞微环境的治疗策略的重要性。