论文标题:鼻咽癌干细胞的初步研究
Preliminary Study of Tumor Stem Cells in Nasopharyngeal Carcinoma
论文作者
论文导师 姚开泰,论文学位 博士,论文专业 分子病理学
论文单位 第一军医大学,点击次数 74,论文页数 110页File Size7429K
2006-04-30论文网 http://www.lw23.com/lunwen_829496522/
stem cells;tumor stem cells;carcinogenesis;ABCG_2;microarray
2002年，Al-Hajj发现人乳腺癌组织中，肿瘤细胞存在不同表型，只有一小群表型为ESA~+CD44~+CD24~-的细胞亚群，能在裸鼠体内形成移植瘤，第一次证实了实体瘤干细胞的存在。此后，人脑胶质瘤干细胞、前列腺癌干细胞相继发现。肿瘤干细胞的存在，改变了我们对肿瘤的认识。肿瘤组织中的肿瘤细胞存在功能上的异质性，只有一小群肿瘤干细胞能形成肿瘤，大部分细胞为非肿瘤干细胞；肿瘤干细胞生成肿瘤时，分裂产生大量的非肿瘤干细胞，重建肿瘤组织的异质性。肿瘤干细胞是肿瘤转移和复发的根源。肿瘤干细胞可能来源与正常组织干细胞的突变。分离和鉴定肿瘤干细胞成为肿瘤研究的热点。 与EB病毒感染相关的鼻咽癌(nasopharyngeal carcinoma，NPC)是高发于我国南方及东南亚地区的鼻咽部低分化鳞癌，虽然鼻咽癌的研究有了极大的进展，其5年生存率仍徘徊于50-60％，并未得到根本性的改善。导致鼻咽癌治疗失败的主要原因是远处转移和局部复发。鼻咽癌是否存在肿瘤干细胞，尚无文献报道，本实验将对此进行探讨。 目前肿瘤干细胞的研究多借鉴于正常干细胞的标志物。而正常鼻咽上皮干细胞研究不多、其标志物不清楚，直接分离鼻咽癌干细胞存在难度，只能从干细胞功能特性着手。造血干细胞的研究发现，干细胞能将荧光染料Hoechst 33342泵出细胞外，在流式细胞仪中显示为小群侧群(side population，SP)细胞。研究表明，侧群细胞的大部分细胞为造血干细胞，而且，Hoechst染料的泵出是通过ABC转运蛋白ABCG的作用产生。由于在肌肉、骨骼、胰腺等多种组织中都发现SP细胞的存在，并具有干细胞的特性，因此，引起SP表征的ABCG_2蛋白被认为是干细胞的通用标志物。我们对鼻咽癌细胞株5-8F和6-10B细胞，进行流式细胞仪检测，显示NPC中ABCG_2~+细胞的含量为1—2％，与文献报道的实体瘤细胞中SP细胞为1％—20％相似。为此，我们拟通过分离鼻咽癌细胞株中的ABCG_2~+细胞，检测其在裸鼠体内成瘤能力，探讨鼻咽癌细胞株中ABCG_2~+细胞的肿瘤干细胞特征。 第一章 NPC细胞株中ABCG_2~+与ABCG_2~-细胞的分选、鉴定及其成瘤能力的比较 1．NPC细胞株中ABCQ_2~+与ABCG_2~-细胞的分选和鉴定
In the paper of "Prospective identification of tumorigenic breast caner cells" published on PNAS by 2002, the author, Al-Hajj, demonstrated that there are different subpopulation in the breast cancers and only a small set of subpopulation (ESA~+CD44~+CD24~-) can generate tumors in nude mice. These tumors, similar to that of the original patient specimens, consist of heterogeneous cells. It is the first time that the existence of tumor stem cells was confirmed. Thereafter, Hemmati HD and Singh SK identified the brain tumor stem cells in 2003. The facts that tumor stem cells can be identified in somatic tumors made a great change on cancer therapy in our mind. The confirming tumor stem cell has important influence on the tumor research and therapy. If tumors are derived from tumor stem cells and tumor metastases come from a set of tumor stem cells, therapy of tumors must aim at tumor stem cells and eliminates them. If the tumor stem cells have not been cleared, then relapse and metastasis may be inevitable. Therefore, isolation and identification of tumor stem cells has become a new hot spot in tumor research.Nasopharyngeal carcinoma (NPC) is an endemic cancer with high incidence in Southeast Asia and Southern China, which obviously shows an ethnic aggregation and geographic distribution. Nasopharyngeal carcinogenesis is a multistage process involving interactions with multiple factors. Epstein-Barr virus (EBV), some chemical carcinogens and genetic factors are all thought to be closely associated with NPC. A clinical characteristic of NPC is early metastasis to cervical lymph nodes and high incidence of remote metastasis. Although great progress in the radiotherapy and imaging diagnosis of NPC have been made in the late 90s, the cure rate of NPC has not been improved yet and 5 year survival rate still remained around 50-60%. Despite of improvements on treatment modalities, local recurrences and remote metastasis occur frequently in NPC patients, which are a leading cause of death. Till now, there are no articles reported that there exist tumor stem cells in NPC. Identification of
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