A mechanism linking Id2-TGFβ crosstalk to reversible adaptive plasticity in neuroblastoma.
A mechanism linking Id2-TGFβ crosstalk to reversible adaptive plasticity in neuroblastoma.
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DOI：
10.1371/journal.pone.0083521
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sandler AD
中科院分区：
文献类型：
--
作者：
Chakrabarti L;Wang BD;Lee NH;Sandler AD
高危神经母细胞瘤在不利的生长条件下生存的能力和多模式治疗已经产生了一种难以捉摸的儿童癌症，预后非常差。一个新的现象，使神经母细胞瘤生存的选择压力是其可逆的适应性可塑性的能力。这种可塑性允许细胞在高度增殖的锚定依赖性（AD）和缓慢生长的抗失巢凋亡的锚定非依赖性（AI）表型之间转变。这两种表型都存在于已建立的小鼠和人类肿瘤中。小鼠Neuro 2a细胞系中两种细胞表型的差异基因表达谱描绘了AD细胞中增殖或AI细胞中酪氨酸激酶激活/凋亡抑制的途径。AD细胞中分化抑制因子2（Inhibitor of differentiation 2，Id 2）过表达20倍，而AI细胞中PI 3 K/Akt、Erk、Bcl 2和整合素等抗失巢凋亡基因表达上调。类似地，在人神经母细胞瘤细胞系SK-N-SH和IMR-32的AD和AI表型中以及在原发性人肿瘤标本中也观察到Id 2和其他感兴趣基因的差异表达。AD细胞中Id 2的强制下调或AI细胞中Id 2的过度表达诱导细胞获得其他表型的特征。Id 2结合TGFβ和Smad 2/3两者，并且似乎至少部分地通过TGFβ/Smad途径的负调节来维持增殖表型。同时靶向控制可逆适应性可塑性的差异分子途径导致显微镜下疾病的50%治愈，并延迟了已建立的小鼠神经母细胞瘤肿瘤的肿瘤生长。我们提出了一种机制，说明可逆的适应性可塑性和分子基础的联合靶向治疗神经母细胞瘤。
The ability of high-risk neuroblastoma to survive unfavorable growth conditions and multimodal therapy has produced an elusive childhood cancer with remarkably poor prognosis. A novel phenomenon enabling neuroblastoma to survive selection pressure is its capacity for reversible adaptive plasticity. This plasticity allows cells to transition between highly proliferative anchorage dependent (AD) and slow growing, anoikis-resistant anchorage independent (AI) phenotypes. Both phenotypes are present in established mouse and human tumors. The differential gene expression profile of the two cellular phenotypes in the mouse Neuro2a cell line delineated pathways of proliferation in AD cells or tyrosine kinase activation/ apoptosis inhibition in AI cells. A 20 fold overexpression of inhibitor of differentiation 2 (Id2) was identified in AD cells while up-regulation of genes involved in anoikis resistance like PI3K/Akt, Erk, Bcl2 and integrins was observed in AI cells. Similarly, differential expression of Id2 and other genes of interest were also observed in the AD and AI phenotypes of human neuroblastoma cell lines, SK-N-SH and IMR-32; as well as in primary human tumor specimens. Forced down-regulation of Id2 in AD cells or overexpression in AI cells induced the cells to gain characteristics of the other phenotype. Id2 binds both TGFβ and Smad2/3 and appears critical for maintaining the proliferative phenotype at least partially through negative regulation of the TGFβ/Smad pathway. Simultaneously targeting the differential molecular pathways governing reversible adaptive plasticity resulted in 50% cure of microscopic disease and delayed tumor growth in established mouse neuroblastoma tumors. We present a mechanism that accounts for reversible adaptive plasticity and a molecular basis for combined targeted therapies in neuroblastoma.
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