Chakrabarti Lina, Wang Bi-Dar, Lee Norman H, Sandler Anthony D
The Joseph E. Robert Center for Surgical Care, Children's National Medical Center, Washington, D.C., United States of America ; The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, D.C., United States of America.
Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, D.C., United States of America.
PLoS One. 2013 Dec 23;8(12):e83521. doi: 10.1371/journal.pone.0083521. eCollection 2013.
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.
高危神经母细胞瘤在不利生长条件下存活以及抵抗多模态疗法的能力，造就了一种难以捉摸且预后极差的儿童癌症。一种使神经母细胞瘤能够在选择压力下存活的新现象是其具有可逆性适应性可塑性的能力。这种可塑性使细胞能够在高度增殖的锚定依赖性（AD）表型和生长缓慢、抗失巢凋亡的锚定独立性（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Neuro2a细胞系中这两种细胞表型的差异基因表达谱描绘了AD细胞中的增殖途径或AI细胞中的酪氨酸激酶激活/凋亡抑制途径。在AD细胞中发现分化抑制因子2（Id2）过表达20倍，而在AI细胞中观察到参与抗失巢凋亡的基因如PI3K/Akt、Erk、Bcl2和整合素上调。同样，在人类神经母细胞瘤细胞系SK-N-SH和IMR-32的AD和AI表型中，以及在原发性人类肿瘤标本中也观察到Id2和其他相关基因的差异表达。在AD细胞中强制下调Id2或在AI细胞中过表达Id2会诱导细胞获得另一种表型的特征。Id2与TGFβ和Smad2/3结合，并且似乎至少部分地通过对TGFβ/Smad途径的负调控对维持增殖表型至关重要。同时靶向控制可逆性适应性可塑性的差异分子途径，在已建立的小鼠神经母细胞瘤肿瘤中使微小疾病的治愈率达到50%并延缓了肿瘤生长。我们提出了一种解释可逆性适应性可塑性的机制以及神经母细胞瘤联合靶向治疗的分子基础。
