Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes.
Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes.
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DOI：
10.1038/onc.2012.588
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发表时间：
2013-11-21
期刊：
影响因子：
8
通讯作者：
Alman, B. A.
中科院分区：
文献类型：
--
作者：
Ho, L.;Ali, S. A.;Al-Jazrawe, M.;Kandel, R.;Wunder, J. S.;Alman, B. A.
初级纤毛可以作为hedgehog（Hh）信号通路的负或正调节器。许多软骨肿瘤的特征在于Hh通路的异常激活。在这里，我们报告说，初级纤毛的存在下发生在低频率（12.4%）的肿瘤软骨细胞从恶性软骨肉瘤，软骨细胞从正常关节软骨（67.7%）相比。为了确定初级纤毛在软骨瘤形成中的功能，我们研究了由软骨细胞特异性过表达Gli 2（Hh通路的下游转录激活因子）在小鼠中形成的良性软骨肿瘤。Col 2A 1-Gli 2小鼠与Ift 88 +/−小鼠杂交，后者显示出纤毛发生的部分缺失。令人惊讶的是，在Ift 88 +/−小鼠中发生的软骨肿瘤与Col 2A 1-Gli 2小鼠中发生的软骨肿瘤在表型上相似。与Col 2A 1-Gli 2或Ift 88 +/−小鼠相比，在Col 2A 1-Gli 2; Ift 88 +/−小鼠中观察到Hh通路的进一步激活，这与软骨肿瘤的发生率增加有关。软骨肉瘤在外植体培养中建立，并用水合氯醛治疗，这破坏了功能性初级纤毛。因此，治疗导致Hh信号通路的过度活跃，以及可能促进肿瘤生长的细胞变化。初级纤毛功能抑制肿瘤软骨细胞中的Hh信号传导。Hh信号的激活足以诱导良性软骨肿瘤，而无需另一致癌起始事件。此外，由于初级纤毛抑制软骨肉瘤中的Hh通路激活，因此抑制适当纤毛功能的细胞机制在维持肿瘤表型中可能是重要的。
Primary cilia can act as either a negative or positive regulator of the hedgehog (Hh) signaling pathway. Many cartilage tumors are characterized by abnormal activation of the Hh pathway. Here, we report that the presence of primary cilia occurs at a low frequency (12.4%) in neoplastic chondrocytes from malignant human chondrosarcomas, compared with chondrocytes from normal articular cartilage (67.7%). To determine the function of primary cilia in cartilaginous neoplasia, we studied benign cartilage tumors that are formed in mice by chondrocyte-specific overexpression of Gli2, a downstream transcriptional activator of the Hh pathway. Col2A1-Gli2 mice were crossed with Ift88+/− mice, which display a partial loss of ciliogenesis. Surprisingly, cartilage tumors developed in Ift88+/− mice that were phenotypically similar to those that arise in Col2A1-Gli2 mice. Further activation of the Hh pathway was observed in Col2A1-Gli2; Ift88+/− mice compared with either Col2A1-Gli2 or Ift88+/− mice, which was associated with an increased incidence of cartilage tumors. Chondrosarcomas were established in explant cultures, and treated with choral hydrate, which disrupts the functional primary cilia. Thus, treatment resulted in hyperactivity of the Hh signaling pathway, as well as cellular changes that could promote tumor growth. Primary cilia functions to inhibit Hh signaling in neoplastic chondrocytes. The activation of Hh signaling is sufficient to induce benign cartilage tumors without another oncogenic initiating event. Moreover, as primary cilia suppress Hh pathway activation in chondrosarcoma, cellular mechanisms inhibiting proper cilia function may be important in maintaining the neoplastic phenotype.
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DOI：
10.1002/ar.20634
发表时间：
2008-09-01
影响因子：
2
作者：
Serra, Rosa
通讯作者：
Serra, Rosa
影响因子：
3.8
作者：
Moser JJ;Fritzler MJ;Rattner JB
通讯作者：
Rattner JB
影响因子：
7
作者：
Pauli, C.;Whiteside, R.;Heras, F. L.;Nesic, D.;Koziol, J.;Grogan, S. P.;Matyas, J.;Pritzker, K. P. H.;D'Lima, D. D.;Lotz, M. K.
通讯作者：
Lotz, M. K.
影响因子：
37.3
作者：
Dormoy V;Danilin S;Lindner V;Thomas L;Rothhut S;Coquard C;Helwig JJ;Jacqmin D;Lang H;Massfelder T
通讯作者：
Massfelder T
影响因子：
3.7
作者：
Pansuriya TC;Oosting J;Krenács T;Taminiau AH;Verdegaal SH;Sangiorgi L;Sciot R;Hogendoorn PC;Szuhai K;Bovée JV
通讯作者：
Bovée JV