LRP5 Signaling in Osteosarcomagenesis: a Cautionary Tale of Translation from Cell Lines to Tumors.
LRP5 Signaling in Osteosarcomagenesis: a Cautionary Tale of Translation from Cell Lines to Tumors.
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DOI：
10.1016/j.tranon.2016.08.010
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发表时间：
2016-10
影响因子：
5
通讯作者：
Jones, Kevin B.
中科院分区：
文献类型：
--
作者：
Horne, Logan;Avilucea, Frank R.;Jin, Huifeng;Barrott, Jared J.;Smith-Fry, Kyllie;Wang, Yanliang;Hoang, Bang H.;Jones, Kevin B.
之前的报告记录了骨肉瘤 (OS) 组织中低密度脂蛋白受体相关蛋白 5 (LRP5) 的表达。这种 Wnt 受体的表达与转移性疾病和较差的无病生存率相关。显性失活 LRP5 (dnLRP5) 缺乏天然蛋白的膜结合域，因此可作为 Wnt 配体的可溶性受体海绵，强制表达，减少骨肉瘤细胞系的体外细胞侵袭和体内异种移植肿瘤生长。在这里，我们使用表达和不表达 dnLRP5 的基因工程小鼠骨肉瘤发生模型来评估肿瘤发生受到影响的程度以及 Wnt/β-catenin 信号传导是否被规避或维持。每组小鼠患骨肉瘤的最终患病率相似，但表达 dnLRP5 的小鼠的潜伏期略有增加。在组织学上，尽管之前有报道称 dnLRP5 骨肉瘤细胞在体外特异性地经历间充质到上皮的转变，但各组之间没有差异。最后，免疫组织化学显示胞浆和核 β-连环蛋白以及核 Cyclin D1 的存在，这些标记物与保留的 Wnt/β-连环蛋白信号一致，尽管细胞表面接收 Wnt 信号配体受到组成性阻断。这些数据表明，规范的 Wnt 信号在 OS 进展中发挥着重要作用，虽然信号通路中单个节点的阻断可以对单个细胞系产生巨大影响，但真正的肿瘤很容易逃避这种集中攻击。
Previous reports document expression of low-density lipoprotein receptor-related protein 5 (LRP5) in osteosarcoma (OS) tissue. Expression of this Wnt receptor correlated with metastatic disease and poor disease-free survival. Forced expression of dominant-negative LRP5 (dnLRP5), which lacks the membrane binding domain of the native protein and therefore functions as a soluble receptor-sponge for Wnt ligands, reduced in vitro cellular invasion and in vivo xenograft tumor growth for osteosarcoma cell lines. Here, we use a genetically engineered mouse model of osteosarcomagenesis with and without expression of dnLRP5 to assess to what degree tumorigenesis is affected and whether Wnt/β-catenin signaling is circumvented or maintained. Each cohort of mice developed osteosarcoma at a similar ultimate prevalence, but after a slightly increased latency in those also expressing dnLRP5. On histology, there was no difference between groups, despite previous reports that the dnLRP5 osteosarcoma cells specifically undergo a mesenchymal-to-epithelial transition in vitro. Finally, immunohistochemistry showed the presence of cytosolic and nuclear β-catenin and nuclear Cyclin D1, markers consistent with preserved Wnt/β-catenin signaling despite constitutive blockade of the cell surface receipt of Wnt signaling ligand. These data suggest that canonical Wnt signaling plays a role in OS progression and that while blockade of singular nodes in signaling pathways can have dramatic effects on individual cell lines, real tumors readily evade such focused attacks.
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DOI：
10.1073/pnas.0805462105
发表时间：
2008-08-19
影响因子：
11.1
作者：
Berman, Seth D.;Calo, Eliezer;Lees, Jacqueline A.
通讯作者：
Lees, Jacqueline A.
影响因子：
64.5
作者：
Nakashima, K;Zhou, X;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML
影响因子：
8
作者：
通讯作者：
--
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW