Notch signaling deregulation in multiple myeloma: A rational molecular target.
Notch signaling deregulation in multiple myeloma: A rational molecular target.
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DOI：
10.18632/oncotarget.5025
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发表时间：
2015-09-29
期刊：
影响因子：
--
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;Garavelli S;Platonova N;Paoli A;Basile A;Taiana E;Neri A;Chiaramonte R
尽管最近的治疗进展，多发性骨髓瘤（MM）仍然是一种无法治愈的肿瘤，由于内在或获得性抵抗治疗。骨髓瘤细胞在骨髓环境中的定位允许肿瘤细胞和非肿瘤骨髓细胞之间的直接相互作用，从而促进肿瘤细胞生长、存活、骨病、获得耐药性和随后的复发。根据肿瘤标记物或表现为浆细胞白血病，20%的MM患者处于治疗失败的高风险。越来越多的证据表明Notch信号在多发性骨髓瘤的发生和发展中起着关键作用。与其他Notch相关的恶性肿瘤不同，大多数患者在Notch通路成员中携带功能获得突变，在MM细胞中，由于Notch受体和配体的表达增加，Notch信号被异常激活；值得注意的是，这也会导致周围基质细胞中Notch信号的激活，从而促进骨髓瘤细胞的增殖、存活和迁移，以及骨病和内在和获得性药物耐药性。在这里，我们回顾了关于MM中Notch信号失调的机制和影响的最新发现，并提供了旨在抑制Notch信号的治疗策略的基本原理，以及对目前可用的Notch定向方法的完整概述。
Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches.