Inactivation of Patched1 in mice leads to development of gastrointestinal stromal-like tumors that express Pdgfrα but not kit.
Inactivation of Patched1 in mice leads to development of gastrointestinal stromal-like tumors that express Pdgfrα but not kit.
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DOI：
10.1053/j.gastro.2012.09.061
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发表时间：
2013-01
期刊：
影响因子：
29.4
通讯作者：
Hahn H
中科院分区：
文献类型：
--
作者：
Pelczar P;Zibat A;van Dop WA;Heijmans J;Bleckmann A;Gruber W;Nitzki F;Uhmann A;Guijarro MV;Hernando E;Dittmann K;Wienands J;Dressel R;Wojnowski L;Binder C;Taguchi T;Beissbarth T;Hogendoorn PC;Antonescu CR;Rubin BP;Schulz-Schaeffer W;Aberger F;van den Brink GR;Hahn H
一部分胃肠道间质瘤 (GIST) 过度表达 PDGFRA 而不是 KIT。目前尚不清楚这是否反映了 PDGFRA 和 KIT 途径的互补致癌潜力，或 GIST 细胞起源的异质性。同样未知的是在许多 GIST 中发现的激活的 Hedgehog (HH)/PATCHED1 (PTCH) 信号传导的重要性。使用由溶菌酶 M (LysM) 启动子驱动的 Cre 重组酶对小鼠 Ptch 进行条件灭活。使用 R26R-LacZ 报告小鼠进行谱系追踪。通过原位杂交、免疫组织化学、蛋白质印迹和 qRT-PCR 来表征肿瘤。通过克隆形成测定评估细胞转化。 LysM 表达细胞中 Ptch 失活导致伊马替尼反应性肿瘤的 GIST 样定位和组织学变化。除了 Hh 信号传导的激活之外，肿瘤还表现出 Pdgfrα 的过度表达和激活，但 Kit 没有过度表达和激活。谱系追踪显示表达 LysM 的肠道细胞呈 Kit 阴性。这些细胞与 Kit 阳性的 Cajal 间质细胞 (ICC) 并列，有时共表达 Pdgfrα。与 KIT 不同，PDGFRA 在细胞转化中与 HH 信号传导合作。 Ptch 突变导致小鼠体内形成 Pdgfrα 阳性 Kit 阴性 GIST 样肿瘤。这些肿瘤的发生可能是由于肠道中 Kit 阴性细胞的 Hh 和 Pdgfrα 通路之间的协同作用。
A fraction of gastrointestinal stromal tumors (GIST) overexpress PDGFRA rather than KIT. Presently it is unknown if this reflects a complementary oncogenic potential of PDGFRA and KIT pathways, or heterogeneity in the cellular origin of GIST. Similarly unknown is the significance of activated Hedgehog (HH)/PATCHED1 (PTCH) signaling found in many GIST. Mouse Ptch was conditionally inactivated using a Cre recombinase driven by the lysozyme M (LysM) promoter. Lineage tracing was done using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, Western blot and qRT-PCR. Cellular transformation was assessed by clonogenic assay. Inactivation of Ptch in LysM-expressing cells resulted in imatinib-responsive tumors of GIST-like localization and histology. In addition to activation of Hh signaling, the tumors showed overexpression and activation of Pdgfrα, but not of Kit. Lineage tracing revealed that LysM-expressing intestinal cells were Kit-negative. These cells were juxtapposed with Kit-positive interstitial cells of Cajal (ICC) and sometimes co-expressed Pdgfrα. In contrast to KIT, PDGFRA cooperated with HH signaling in cellular transformation. Mutations in Ptch result in formation of Pdgfrα-positive Kit-negative GIST-like tumors in mice. These tumors may develop due to cooperativity between Hh and Pdgfrα pathways from Kit-negative cells in the intestine.
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影响因子：
11.2
作者：
Schnidar H;Eberl M;Klingler S;Mangelberger D;Kasper M;Hauser-Kronberger C;Regl G;Kroismayr R;Moriggl R;Sibilia M;Aberger F
通讯作者：
Aberger F
影响因子：
11.2
作者：
Meza-Zepeda, Leonardo A.;Kresse, Stine H.;Myklebost, Ola
通讯作者：
Myklebost, Ola
影响因子：
7.5
作者：
Chu, PG;Wu, E;Weiss, LM
通讯作者：
Weiss, LM
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
29.4
作者：
Bardsley MR;Horváth VJ;Asuzu DT;Lorincz A;Redelman D;Hayashi Y;Popko LN;Young DL;Lomberk GA;Urrutia RA;Farrugia G;Rubin BP;Ordog T
通讯作者：
Ordog T