Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model.
Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model.
复制标题
DOI：
10.1016/j.ccr.2008.12.006
复制
发表时间：
2009-01-06
期刊：
影响因子：
50.3
通讯作者：
Parada, Luis F.
中科院分区：
文献类型：
--
作者：
Llaguno, Sheila Alcantara;Chen, Jian;Kwon, Chang-Hyuk;Jackson, Erica L.;Li, Yanjiao;Burns, Dennis K.;Alvarez-Buylla, Arturo;Parada, Luis F.
恶性星形细胞瘤是一种浸润性的、无法治愈的脑肿瘤。尽管具有深远的治疗意义，但起源细胞的身份尚未严格确定。我们之前报道了基于人类星形细胞瘤相关肿瘤抑制因子p53、Nf1和Pten条件失活的小鼠模型，其中通过体细胞杂合性丧失，突变小鼠产生100%外显率的肿瘤。在本研究中，我们发现神经干/祖细胞中的肿瘤抑制因子失活是诱导星形细胞瘤形成的必要和充分条件。我们在体内证明了转化细胞及其后代在肿瘤发生过程中经历浸润和多谱系分化。来自症状前小鼠的抑瘤杂合神经干/祖细胞培养物显示出异常生长优势和分化改变，从而确定了致瘤前细胞群。鉴定产生肿瘤的原始细胞以及它是否是一种有限的细胞类型对了解癌症的发展具有至关重要的意义。这些知识也是严格研究肿瘤发生机制所必需的。使用完全渗透的小鼠模型，我们确定神经干/祖细胞为癌症起始细胞，并深入了解这些肿瘤的行为。我们还报道了恶性星形细胞瘤小鼠模型，其中肿瘤抑制因子在胚胎期、出生后早期或成年期失活诱导肿瘤形成，并证明肿瘤细胞在肿瘤内分化的能力。我们对症状前突变祖细胞培养的研究表明，早在临床表现出现之前，该疾病就可能传播并获得生长优势。
Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell(s) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of human astrocytoma-relevant tumor suppressors p53, Nf1, and Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors with 100% penetrance. In the present study, we show that tumor suppressor inactivation in neural stem/progenitor cells is both necessary and sufficient to induce astrocytoma formation. We demonstrate in vivo that transformed cells and their progeny undergo infiltration and multi-lineage differentiation during tumorigenesis. Tumor suppressor heterozygous neural stem/progenitor cultures from pre-symptomatic mice show aberrant growth advantage and altered differentiation, thus identifying a pre-tumorigenic cell population. Identification of the original cell that gives rise to a tumor and whether it is a limited cell type has crucial implications for understanding cancer development. This knowledge is also requisite for rigorous investigation of tumor initiation mechanisms. Using fully penetrant mouse models, we identify neural stem/progenitor cells as cancer-initiating cells and derive insight into the behavior of these tumors. We also report malignant astrocytoma mouse models wherein tumor suppressor inactivation at embryonic, early postnatal, or adult ages induces tumor formation, and demonstrates the capacity of tumor cells to differentiate within the tumor. Our studies on pre-symptomatic mutant progenitor cultures indicate that the disease could be disseminating and acquire growth advantage long before the onset of clinical manifestations.
登录
查看更多内容
影响因子：
82.9
作者：
Eriksson, PS;Perfilieva, E;Gage, FH
通讯作者：
Gage, FH
影响因子：
10.5
作者：
Dai, C;Celestino, JC;Holland, EC
通讯作者：
Holland, EC
影响因子：
11.5
作者：
Fomchenko, Elena I.;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
30.8
作者：
Reilly, KM;Loisel, DA;Jacks, T
通讯作者：
Jacks, T
影响因子：
64.8
作者：
Sanai, N;Tramontin, AD;Alvarez-Buylla, A
通讯作者：
Alvarez-Buylla, A