Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with β-Catenin Activation or Wt1 Ablation and Igf2 Upregulation.
Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with β-Catenin Activation or Wt1 Ablation and Igf2 Upregulation.
复制标题
DOI：
10.1016/j.neo.2015.12.001
复制
发表时间：
2016-02
期刊：
影响因子：
4.8
通讯作者：
Huff, Vicki
中科院分区：
文献类型：
--
作者：
Huang, Le;Mokkapati, Sharada;Hu, Qianghua;Ruteshouser, E. Cristy;Hicks, M. John;Huff, Vicki
肾母细胞瘤是一种常见的儿童肾脏肿瘤，被认为起源于未分化的肾间质。可变的肿瘤组织学和显示不同基因表达谱的肿瘤亚群的鉴定表明肿瘤可能出现在间充质分化的不同阶段，并且这种个体发生的变异性影响肿瘤病理学、生物学和临床结果。为了测试不同细胞类型在发育中的肾脏中的致瘤潜力，我们使用肾祖细胞特异性Cre重组酶等位基因将Wt 1和Ctnnb 1突变（在Wilms肿瘤中观察到的两种改变）引入胚胎小鼠肾脏中，有和没有双等位基因Igf 2表达，另一种改变在大多数肿瘤中观察到。使用靶向肾单位祖细胞的Cre等位基因来引入稳定β-连环蛋白的Ctnnb 1突变，导致肿瘤的发展，其具有主要的上皮组织学和基因表达谱，其中早期肾间质特征性基因不表达。Wt 1消融和Igf 2双等位基因表达的肾单位祖细胞也具有致瘤性，但显示出更多的三相组织学，并表达早期后肾间充质基因。相比之下，将这些遗传改变靶向基质祖细胞不会导致肿瘤。这些数据表明，定向肾单位祖细胞可以引起肾母细胞瘤，而定向间质祖细胞的致瘤性较低，这表明表现出主要间质组织学的人类肾母细胞瘤在定向为间质谱系之前就起源于间质。
Wilms tumor, a common childhood tumor of the kidney, is thought to arise from undifferentiated renal mesenchyme. Variable tumor histology and the identification of tumor subsets displaying different gene expression profiles suggest that tumors may arise at different stages of mesenchyme differentiation and that this ontogenic variability impacts tumor pathology, biology, and clinical outcome. To test the tumorigenic potential of different cell types in the developing kidney, we used kidney progenitor-specific Cre recombinase alleles to introduce Wt1 and Ctnnb1 mutations, two alterations observed in Wilms tumor, into embryonic mouse kidney, with and without biallelic Igf2 expression, another alteration that is observed in a majority of tumors. Use of a Cre allele that targets nephron progenitors to introduce a Ctnnb1 mutation that stabilizes β-catenin resulted in the development of tumors with a predominant epithelial histology and a gene expression profile in which genes characteristic of early renal mesenchyme were not expressed. Nephron progenitors with Wt1 ablation and Igf2 biallelic expression were also tumorigenic but displayed a more triphasic histology and expressed early metanephric mesenchyme genes. In contrast, the targeting of these genetic alterations to stromal progenitors did not result in tumors. These data demonstrate that committed nephron progenitors can give rise to Wilms tumors and that committed stromal progenitors are less tumorigenic, suggesting that human Wilms tumors that display a predominantly stromal histology arise from mesenchyme before commitment to a stromal lineage.
登录
查看更多内容
影响因子：
2.7
作者：
Mugford, Joshua W.;Sipilae, Petra;McMahon, Jill A.;McMahon, Andrew P.
通讯作者：
McMahon, Andrew P.
影响因子：
11.8
作者：
Park, Joo-Seop;Ma, Wenxiu;O'Brien, Lori L.;Chung, Eunah;Guo, Jin-Jin;Cheng, Jr-Gang;Valerius, M. Todd;McMahon, Jill A.;Wong, Wing Hung;McMahon, Andrew P.
通讯作者：
McMahon, Andrew P.
影响因子：
4.6
作者：
Brunskill, Eric W.;Park, Joo-Seop;Potter, S. Steven
通讯作者：
Potter, S. Steven
影响因子：
11.2
作者：
Mokkapati S;Niopek K;Huang L;Cunniff KJ;Ruteshouser EC;deCaestecker M;Finegold MJ;Huff V
通讯作者：
Huff V
影响因子：
5.9
作者：
Kobayashi, Akio;Mugford, Joshua W.;Krautzberger, A. Michaela;Naiman, Natalie;Liao, Jessica;McMahon, Andrew P.
通讯作者：
McMahon, Andrew P.