基于能量代谢的恶性脑胶质瘤干细胞放疗抵抗研究

Malignant glioma is one of the most occuring tumors in central nervous system. Even after receiving the most advanced treatment, including neurosurgery, radiotherapy, and chemotherapy, the mean survival rate remains poor. The radioresistance of cancer stem cells was a major cause of tumor recurrence. Recently, reprogramming energy metabolism has been regarded as a tumor hallmark. Cancer cells rely on glycolysis even if oxygen is available, leading to a state that has been termed Warburg effect.Cancer cells produce lactate via glycolysis, and furthermore, it has shown that tissue lactate content correlates with radioresistance in solid human tumors in the past research. A latest study has demonstrated that the metabolism of glioma stem cells (GSCs) differs from that of nontumorigenic cells. Based on these research results, we assume that GSCs may enhance their radioresistance via lactate as energy resource which is produced from the warburg effect of neighbouring cancer cells. Therefore， three problems are proposed as follows: 1.What is the difference of the radiation impact on energe metabolism between cancer stem cell and nontumorigenic cell? 2. Whether the Warburg effect of glioma provide lactate for GSCs to improve the radioresistance of GSCs? 3. Is it effective to reduce the radioresistance of GSCs by blocking the transportation of lactate? In this study, cancer stem cells will be isolated and identified from glioma cell lines and clinlical samples, which are used to answer the problem that whether blocking the transportation of lactic acid can reduce the radioresistance of tumor stem cells in vivo and in vitro. The research is important to find a novel target for the therapy of malignant glioma.

恶性脑胶质瘤干细胞的放疗抵抗性是治疗后复发的一个重要原因。近年来，特殊的能量代谢被公认为是肿瘤最重要标志之一。肿瘤细胞主要依赖糖酵解进行能量代谢，即使有氧也是如此（Warburg 效应）。肿瘤细胞糖酵解产生乳酸，而且乳酸浓度与肿瘤的放疗抵抗性呈正相关。最近有研究报道胶质瘤干细胞能量代谢方式不同于非干细胞的瘤细胞。基于此，我们推测胶质瘤干细胞可能从周围瘤细胞Warburg效应产生的大量乳酸中获取能量，来提高放疗抵抗性。本研究将围绕以下几个问题展开：放疗对胶质瘤干细胞和非干细胞的肿瘤细胞能量代谢的影响有何差异？胶质瘤干细胞是否利用Warburg效应产生的乳酸作为能量来源，提高放疗抵抗性？针对乳酸转运的环节进行干预，对降低胶质瘤干细胞放疗抵抗性是否有效？针对上述问题，本研究将从胶质瘤细胞株和临床标本中分离鉴定出肿瘤干细胞，在细胞和动物水平研究乳酸转运体能否作为降低肿瘤干细胞放疗抵抗性的靶点。

恶性脑胶质瘤干细胞的放疗抵抗性是治疗后复发的一个重要原因。近年来，特殊的能量代谢被公认为是肿瘤最重要标志之一。肿瘤细胞主要依赖糖酵解进行能量代谢，即使有氧也是如此（Warburg 效应）。肿瘤细胞糖酵解产生乳酸，而且乳酸浓度与肿瘤的放疗抵抗性呈正相关。最近有研究报道胶质瘤干细胞能量代谢方式不同于非干细胞的瘤细胞。基于此，我们推测胶质瘤干细胞可能从周围瘤细胞Warburg 效应产生的大量乳酸中获取能量，来提高放疗抵抗性。本研究将围绕以下几个问题展开：放疗对胶质瘤干细胞和非干细胞的肿瘤细胞能量代谢的影响有何差异？胶质瘤干细胞是否利用 Warburg效应产生的乳酸作为能量来源，提高放疗抵抗性？针对乳酸转运的环节进行干预，对降低胶质瘤干细胞放疗抵抗性是否有效？针对上述问题，本研究从胶质瘤细胞株和临床标本中分离鉴定出肿瘤干细胞，在细胞和动物水平研究乳酸转运体能否作为降低肿瘤干细胞放疗抵抗性的靶点。 我们已经成功建立肿瘤干细胞培养体系，得到胶质瘤干细胞球，下一步按计划进行能量代谢方面的研究。在该项目的执行过程中，我们发现C-fos基因启动子在胶质瘤中有较高的表达效率和特异性，利用C-fos基因启动子联合自杀基因有望开发一种新的胶质瘤治疗方法。基于这些发现，我们正在撰写SCI论文1篇，并申报国家专利1项。