Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis
Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis
复制标题
DOI：
10.1074/jbc.m608900200
复制
发表时间：
2007-03-02
影响因子：
4.8
通讯作者：
Galve-Roperh, Ismael
中科院分区：
文献类型：
--
作者：
Aguado, Tania;Carracedo, Arkaitz;Galve-Roperh, Ismael
胶质瘤干细胞是胶质瘤的潜在来源之一，因此，消除它们是一种潜在的治疗方法。这是制定有效治疗策略的关键因素。已知大麻素对胶质瘤的抗肿瘤作用依赖于至少两种机制：诱导转化细胞的凋亡和抑制肿瘤血管生成。然而，大麻素是否以人脑胶质瘤干细胞为靶点及其在胶质瘤形成中的潜在影响尚不清楚。在这里，我们展示了来源于多形性胶质母细胞瘤活检组织的胶质瘤干细胞和胶质瘤细胞系U87 MG和U373 MG表达大麻素1型(CB1)和2型(CB2)受体以及内源性大麻素系统的其他元件。在基因芯片实验中，CB受体的激活改变了参与干细胞增殖和分化调控的基因的表达。大麻素激动剂HU-210和JWH-133以CB受体依赖的方式促进胶质细胞分化，表现为S-100β和胶质纤维酸性蛋白表达细胞数量增加。同时，大麻素减少了神经上皮祖细胞标记物Nestin的表达。此外，大麻素攻击降低了胶质瘤干细胞在体内启动胶质瘤形成的效率，这一发现与二次异种移植中神经球形成和细胞增殖减少有关。来源于大麻素治疗的肿瘤干细胞的胶质瘤具有一组神经标记物的特征，并证明有更多的分化表型和伴随的巢蛋白表达的减少。总体而言，我们的结果表明，大麻素可以靶向胶质瘤干细胞样细胞，促进其分化，抑制胶质瘤的形成，从而进一步支持它们在恶性胶质瘤治疗中的潜在应用。
Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an. essential factor for the development of efficient therapeutic strategies. Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis. However, whether cannabinoids target human glioma stem cells and their potential impact in gliomagenesis are unknown. Here, we show that glioma stem-like cells derived from glioblastoma multiforme biopsies and the glioma cell lines U87MG and U373MG express cannabinoid type 1 (CB1) and type 2 (CB2) receptors and other elements of the endocannabinoid system. In gene array experiments, CB receptor activation altered the expression of genes involved in the regulation of stem cell proliferation and differentiation. The cannabinoid agonists HU-210 and JWH-133 promoted glial differentiation in a CB receptor-dependent manner as shown by the increased number of S-100 beta- and glial fibrillary acidic protein-expressing cells. In parallel, cannabinoids decreased the cell population expressing the neuroepithelial progenitor marker nestin. Moreover, cannabinoid challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo, a finding that correlated with decreased neurosphere formation and cell proliferation in secondary xenografts. Gliomas derived from cannabinoid-treated cancer stem-like cells were characterized with a panel of neural markers and evidenced a more differentiated phenotype and a concomitant decrease in nestin expression. Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.