Notch signaling drives multiple myeloma induced osteoclastogenesis.
Notch signaling drives multiple myeloma induced osteoclastogenesis.
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DOI：
10.18632/oncotarget.2084
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发表时间：
2014-11-15
期刊：
影响因子：
--
通讯作者：
Chiaramonte R
中科院分区：
文献类型：
--
作者：
Colombo M;Thümmler K;Mirandola L;Garavelli S;Todoerti K;Apicella L;Lazzari E;Lancellotti M;Platonova N;Akbar M;Chiriva-Internati M;Soutar R;Neri A;Goodyear CS;Chiaramonte R
多发性骨髓瘤（MM）与骨质破坏密切相关。一旦迁移到骨髓，MM细胞通过募集和成熟破骨细胞前体使骨形成和再吸收失衡。Notch通路在不同类型的癌症中起关键作用，并驱动与MM相关的几个生物学过程，包括骨髓内的细胞定位、增殖、存活和药理学抗性。在这里，我们提出的证据表明，MM可以有效地驱动破骨细胞的同时激活Notch信号转导的肿瘤细胞和破骨细胞通过异常表达的Notch配体属于锯齿状家族。MM细胞中的主动Notch信号传导诱导关键破骨细胞生成因子RANKL的分泌，其可在基质细胞存在下增强。反过来，MM细胞衍生的RANKL导致破骨细胞前体中其受体RANK和Notch2的上调。Notch2通过促进自分泌RANKL信号传导刺激破骨细胞分化。最后，MM细胞通过Jagged配体表达也可以通过直接接触激活前破骨细胞中的Notch信号传导。MM诱导的破骨细胞生成中肿瘤细胞和前破骨细胞之间的这种协同作用可以通过沉默肿瘤源性锯齿蛋白1和2来破坏。这些结果使得Jagged配体成为MM中新的有希望的治疗靶点，以对比骨疾病和相关的共病。
Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors. The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance. Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact. Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.
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影响因子：
20.3
作者：
Moreaux, Jerome;Hose, Dirk;Klein, Bernard
通讯作者：
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影响因子：
11.2
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10.1016/j.bbamcr.2012.10.018
发表时间：
2013-01-01
影响因子：
5.1
作者：
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通讯作者：
Park, Hee-Sae
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20.3
作者：
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通讯作者：
Dörken, B