Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche.
Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche.
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DOI：
10.18632/oncotarget.10820
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发表时间：
2016-08-30
期刊：
影响因子：
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通讯作者：
Chiaramonte R
中科院分区：
文献类型：
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作者：
Colombo M;Galletti S;Bulfamante G;Falleni M;Tosi D;Todoerti K;Lazzari E;Crews LA;Jamieson CH;Ravaioli S;Baccianti F;Garavelli S;Platonova N;Neri A;Chiaramonte R
由于核型高度不稳定性，多发性骨髓瘤细胞的生长依赖于内在的侵袭性，或者依赖于骨髓 (BM) 生态位的支持。我们和其他小组提供的证据表明，Notch 信号传导与肿瘤细胞生长、药理学耐药性、骨髓中的定位/再循环和骨疾病有关。这项研究表明，Notch 信号传导成员（JAG1、NOTCH2、HES5 和 HES6）的高基因表达水平与恶性进展或高风险疾病相关，Notch 信号传导可能通过增加白细胞介素 6 (IL-6) 的 BM 水平参与骨髓瘤进展，白细胞介素 6 (IL-6) 是骨髓瘤细胞生长和存活的主要参与者。事实上，通过骨髓瘤患者基因表达谱的相关分析和免疫组织化学研究证实的体外结果表明，Notch 信号传导控制能够自主产生 IL-6 的骨髓瘤细胞以及周围的 BM 基质细胞中的 IL-6 基因表达。在这两种情况下，Notch 信号传导激活可能由骨髓瘤细胞衍生的锯齿状配体触发。 Notch 信号传导在骨髓瘤相关 BM 中正控制 IL-6 的证据使得该通路成为骨生态位肿瘤定向重编程的关键介质。这项工作强化了基于锯齿状配体抑制的新型 Notch 定向治疗多发性骨髓瘤的基本原理。
Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche. We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease. This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche. This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands.