胶质母细胞瘤干性起源的分子生物学研究

Gliomas are the most incident brain tumor in adults. This malignancy has very low survival rates, even when aggressive multimodality therapy consisting of radiotherapy, chemotherapy, and surgical excision is used. Among the gliomas, glioblastoma multiforme (GBM) is the most common and aggressive type, and patients frequently relapse or become refractory to conventional therapies, and median survival is only 12-17 months. Recent studies showed that there is a group of cells, glioma stem cells (GSCs), that plays a central role in tumor development, invasion, metastasis, and drug resistance. These cells have been isolated and characterized as a heterogeneous cell population that have unique features, making them a relevant key in tumor survival. They also show marked capacity for proliferation, self-renewal, and differentiation. Characteristic GSCs can be defined according to their ability to efficiently reconstitute the original tumor when transplanted into immunocompromised mice. However, the precise origin of glioma stem cells still remains elusive. Thanks to new advances in cell and molecular biology, researchers have found that glioma stem cells have many characteristics shared with neural stem cells, such as self-renewal, neurosphere formation, marker expression, multilineage differentiation, high motility, and localization to stem cell microenvironment niches. Therefore, we hypothesized that glioma stem cells may be derived from malignant transformation of neural stem cells. On the basis of above all, we plan to contrast genes expression of Notch, Hedgehog, Wnt, RTK-Akt, PTEN AND Bmi 1 signaling pathway, and find the differentially expression of key genes between glioma stem cells and neural stem cells. Moreover, we intend to interfere with the expression of key gene in glioma stem cells and neural stem cells, and induced neural stem cells into tumor-like cells or blocked tumorigenicity of glioma stem cells. In addition, the expression of tumor specific genes in glioblastoma and tumor-like cells derived from neural stem cells were detected. All these are in order to clarify glioma stem cells may be derived from neural stem cells, and indicate the targets of gene therapy in the field of glioblastoma.

胶质母细胞瘤是常见的原发性恶性颅内肿瘤之一，生长迅速，且5年生存率极低。胶质母细胞瘤组织中存在可以自我更新、增殖的细胞，在肿瘤发生、发展、侵袭、转移及耐药等生物学特性中起主要作用，被称为胶质瘤干细胞。但到目前为止对胶质瘤干细胞的起源知之甚少。近来研究发现，胶质瘤干细胞与神经干细胞具有相似的细胞生物学特征和信号途径，在此基础上，本课题假设胶质瘤干细胞来源于神经干细胞的恶变，其信号途径具有相关性。因此，本课题拟研究胶质瘤干细胞与神经干细胞的Notch、Hedgehog、Wnt、RTK-Akt、PTEN和Bmi 1等相关信号通路基因，寻找胶质瘤干细胞与神经干细胞相关信号通路的关键差异表达基因，并干预关键基因在胶质瘤干细胞和神经干细胞上的表达，诱导神经干细胞肿瘤样变或逆转胶质瘤干细胞的致瘤性，以探讨胶质母细胞瘤干细胞的来源，及其发生发展的分子生物学机制，为胶质母细胞瘤治疗提供可能的基因靶点。

胶质母细胞瘤是常见的原发性恶性颅内肿瘤之一，生长迅速，且5年生存率极低。胶质母细胞瘤组织中存在可以自我更新、增殖的细胞，在肿瘤发生、发展、侵袭、转移及耐药等生物学特性中起主要作用，被称为胶质瘤干细胞。但到目前为止对胶质瘤干细胞的起源知之甚少。近来研究发现，胶质瘤干细胞与神经干细胞具有相似的细胞生物学特征和信号途径，在此基础上，本课题假设胶质瘤干细胞来源于神经干细胞的恶变，其信号途径具有相关性。因此，本课题拟研究胶质瘤干细胞与神经干细胞的Notch、Hedgehog、Wnt、RTK-Akt、PTEN和Bmi 1等相关信号通路基因，寻找胶质瘤干细胞与神经干细胞相关信号通路的关键差异表达基因，并干预关键基因在胶质瘤干细胞和神经干细胞上的表达，诱导神经干细胞肿瘤样变或逆转胶质瘤干细胞的致瘤性，以探讨胶质母细胞瘤干细胞的来源，及其发生发展的分子生物学机制，为胶质母细胞瘤治疗提供可能的基因靶点。