Spontaneous development of intratumoral heterogeneity in a transposon-induced mouse model of glioma.
Spontaneous development of intratumoral heterogeneity in a transposon-induced mouse model of glioma.
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DOI：
10.1111/cas.13579
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发表时间：
2018-05
期刊：
影响因子：
5.7
通讯作者：
Watanabe S
中科院分区：
文献类型：
--
作者：
Sumiyoshi K;Koso H;Watanabe S
神经胶质瘤是成人中最常见的恶性脑癌。基于睡美人（SB）转座子的胶质瘤小鼠模型允许候选基因的有效体内分析。在本研究中，我们开发了一种转座子载体，该载体编码血小板衍生生长因子亚基A（PDGFA）以及针对Nf 1和Trp 53的shRNA（shNf 1/shp 53）的三重组合。通过荧光蛋白的表达监测脑胶质瘤的发生和发展。将该载体转导到新生儿脑室下区（SVZ）的神经祖细胞和干细胞（NPC）中，诱导少突胶质细胞前体细胞增殖，并促进2 - 4个月内高渗透性恶性胶质瘤的形成。从肿瘤中分离的细胞能够形成继发性肿瘤。将编码PDGFA或shNf 1/shp 53的两个转座子载体共电穿孔到NPC中。表达PDGFA或shNf 1/shp 53的细胞用独特的荧光蛋白标记，允许在同一肿瘤内具有不同遗传改变的细胞的空间分布可视化。位于肿瘤中心的肿瘤细胞表达PDGFA的水平高于位于周边的肿瘤细胞，表明PDGFA表达水平的肿瘤内异质性在同一肿瘤内自发形成。栅栏状坏死的肿瘤细胞强烈表达PDGFA，表明PDGFA信号参与胶质瘤的缺氧反应。所开发的转座子载体与任何基因工程小鼠模型兼容，为胶质瘤候选基因的功能分析提供了有用的工具。
Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon‐based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet‐derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2‐4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co‐electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.
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肿瘤基因对神经元和星形胶质细胞的去分化会在小鼠中诱导神经胶质瘤。
DOI：
10.1126/science.1226929
发表时间：
2012-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Friedmann-Morvinski D;Bushong EA;Ke E;Soda Y;Marumoto T;Singer O;Ellisman MH;Verma IM
通讯作者：
Verma IM
ATRX 缺失会促进肿瘤生长并损害神经胶质瘤中的非同源末端连接 DNA 修复。
影响因子：
17.1
作者：
Koschmann C;Calinescu AA;Nunez FJ;Mackay A;Fazal-Salom J;Thomas D;Mendez F;Kamran N;Dzaman M;Mulpuri L;Krasinkiewicz J;Doherty R;Lemons R;Brosnan-Cashman JA;Li Y;Roh S;Zhao L;Appelman H;Ferguson D;Gorbunova V;Meeker A;Jones C;Lowenstein PR;Castro MG
通讯作者：
Castro MG
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Martinho, O.;Longatto-Filho, A.;Lambros, M. B. K.;Martins, A.;Pinheiro, C.;Silva, A.;Pardal, F.;Amorim, J.;Mackay, A.;Milanezi, F.;Tamber, N.;Fenwick, K.;Ashworth, A.;Reis-Filho, J. S.;Lopes, J. M.;Reis, R. M.
通讯作者：
Reis, R. M.
影响因子：
11.2
作者：
Koso, Hideto;Tsuhako, Asano;Watanabe, Sumiko
通讯作者：
Watanabe, Sumiko