Chemotherapy resistance of glioblastoma stem cells
Chemotherapy resistance of glioblastoma stem cells
复制标题
DOI：
10.1038/sj.cdd.4401872
复制
发表时间：
2006-07-01
影响因子：
12.4
通讯作者：
De Maria, R.
中科院分区：
文献类型：
--
作者：
Eramo, A.;Ricci-Vitiani, L.;De Maria, R.
多形性胶质母细胞瘤（GBM）是最具破坏性的癌症之一，中位生存期约为1年。1 GBM由于其位置、侵袭性生物学行为和弥漫性浸润性生长而对治疗提出了独特的挑战。尽管新的手术和放射技术的发展和多种抗肿瘤药物的使用，恶性胶质瘤的治愈仍然难以捉摸。2目前治疗的缺乏疗效反映了胶质母细胞瘤细胞对体外细胞毒性药物的耐药性。此外，胶质母细胞瘤患者肿瘤复发的时间间隔短，表明致瘤细胞能够在没有重大损害的情况下超过治疗。癌症干细胞假说认为，实体瘤完全由具有干细胞特性的一小部分癌细胞维持。癌症干细胞的存在首先在急性髓细胞白血病的背景下得到证实。最近，这一原则也被扩展到其他肿瘤，如乳腺癌和脑癌。6-8据报道，肿瘤干细胞是GBM中唯一的致瘤细胞群，其无限的增殖潜力是肿瘤发展和维持所必需的。因此，这些细胞应该代表主要的治疗靶点，以实现肿瘤的完全根除。如前所述，我们通过机械分离肿瘤组织并在补充有表皮生长因子（EGF）和碱性成纤维细胞生长因子（bFGF）的无血清培养基中培养，从手术标本中分离未分化的GBM细胞（图1a，B）。7分离的细胞在体外和体内扩增和表征。GBM衍生的细胞克隆能够在称为肿瘤球的聚集体中体外生长并保持未分化状态，如干细胞标志物如CD 133和巢蛋白（未显示）的形态和表达所示。通过在免疫受损小鼠中颅内或皮下细胞注射来测定GBM肿瘤球的体内致瘤潜力。GBM干细胞能够产生在抗原表达和组织学组织结构方面与人肿瘤相同的肿瘤（图1c、d和数据未显示）。总之，GBM干细胞的这些特征表明它们可以提供用于研究胶质母细胞瘤对治疗的反应的可靠的体外和体内模型。因此，我们应该研究不同化疗药物对GBM干细胞存活和扩增的影响。
Glioblastoma Multiforme (GBM) is among the most devastating cancers, with a median survival of approximately 1 year. 1 GBM presents unique challenges to therapy due to its location, aggressive biological behavior and diffuse infiltrative growth. Despite the development of new surgical and radiation techniques and the use of multiple antineoplastic drugs, a cure for malignant gliomas remains elusive. 2 The scarce efficacy of current treatments reflects the resistance of glioblastoma cells to cytotoxic agents in vitro. 3, 4 Moreover, the short interval for tumor recurrence in glioblastoma patients suggests that tumorigenic cells are able to overtake the treatments without major damage. The cancer stem cell hypothesis asserts that solid tumors are maintained exclusively by a rare fraction of cancer cells with stem cell properties. The existence of cancer stem cells was first proven in the context of acute myeloid leukemia. 5 More recently, this principle has also been extended to other tumors, such as breast and brain cancer. 6–8 Cancer stem cells have been reported to be the only tumorigenic population in GBM, their unlimited proliferative potential being required for tumor development and maintenance. 8 Thus, these cells should represent the primary therapeutic target in order to achieve complete eradication of the tumor. We isolated undifferentiated GBM cells from surgical specimens (Figure 1a, b) through mechanical dissociation of the tumor tissue and culture in a serum free medium supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) as previously described. 7 Isolated cells were expanded and characterized both in vitro and in vivo. GBM-derived cell clones were able to grow in vitro in aggregates called tumor spheres and maintain an undifferentiated state, as indicated by morphology and expression of stem cell markers such as CD133 and nestin (not shown). The in vivo tumorigenic potential of GBM tumor spheres was assayed by intracranial or subcutaneous cell injection in immunocompromised mice. GBM stem cells were able to generate a tumor identical to the human tumor in terms of antigen expression and histological tissue organization (Figure 1c, d and data not shown). Altogether, these features of GBM stem cells indicate that they may provide a reliable in vitro and in vivo model for studying glioblastoma response to treatments. Therefore, we ought to investigate the effect of different chemotherapeutic agents on GBM stem cell survival and expansion.