Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells.
Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells.
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DOI：
10.1016/j.molonc.2015.10.002
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发表时间：
2016-02
影响因子：
6.6
通讯作者：
Roz L
中科院分区：
文献类型：
--
作者：
Andriani F;Bertolini G;Facchinetti F;Baldoli E;Moro M;Casalini P;Caserini R;Milione M;Leone G;Pelosi G;Pastorino U;Sozzi G;Roz L
肿瘤内的癌细胞在功能上是异质的，并且被定义为癌症起始细胞（CIC）的特定亚群被赋予更高的肿瘤形成潜力。然而，CIC状态在层次上并不稳定，并且在微环境信号下非CIC向CIC的转化可能代表肿瘤侵袭性的决定因素。然而，可塑性在细胞水平上是如何调节的，人们还知之甚少。为了确定肺癌可塑性的决定因素，我们将8种不同的细胞系暴露于TGFβ1以诱导EMT并刺激CD 133 + CIC的调节。我们发现，对TGFβ1治疗的反应是异质的，一些细胞容易转换为干细胞状态（CIC增加1.5-2倍），而其他细胞对刺激无反应。这种反应与原始CIC含量或EMT参与程度无关，但紧密依赖于上皮和间充质特征之间的平衡，如通过CDH 1（E-钙粘蛋白）与SNAI 2的表达比率所测量的。这种平衡的表观遗传调节可以恢复无反应模型对微环境刺激的敏感性，包括体外和体内癌症相关成纤维细胞引起的刺激。特别地，具有部分EMT（混合上皮/间充质表型）特征的细胞的患病率增加的肿瘤被赋予最高的可塑性，并且SNAI 2和CDH 1标志物的特定表达模式鉴定具有较差预后的肿瘤子集。总之，在这里，我们描述了混合上皮/间充质表型与响应外部刺激而转化为干细胞状态之间的联系。这些发现对目前识别具有增加的可塑性的肿瘤的努力具有影响。来自微环境的信号参与调节肺癌中的癌症起始细胞（CIC）。上皮/间充质特征之间的平衡是干细胞表型获得倾向的关键决定因素。上皮/间质平衡的表观遗传修饰可以调节对微环境刺激的反应。E-cadherin和SNAI 2的特定表达模式与NSCLC的最差预后相关。
Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non‐CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFβ1 to induce EMT and stimulate modulation of CD133+ CICs. We show that response to TGFβ1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5–2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E‐cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer‐associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem‐cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity. Signals from the microenvironment are involved in modulation of cancer initiating cells (CICs) in lung cancer. Balance between epithelial/mesenchymal features is a crucial determinant of proclivity to stemness phenotype acquisition. Epigenetic modification of epithelial/mesenchymal balance can regulate response to microenvironmental stimuli. A specific pattern of expression of E‐cadherin and SNAI2 is associated with worst prognosis in NSCLC.
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影响因子：
3.9
作者：
Cieślik M;Hoang SA;Baranova N;Chodaparambil S;Kumar M;Allison DF;Xu X;Wamsley JJ;Gray L;Jones DR;Mayo MW;Bekiranov S
通讯作者：
Bekiranov S
影响因子：
7.3
作者：
Gonzalez DM;Medici D
通讯作者：
Medici D
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.
癌症相关成纤维细胞通过旁分泌信号调节肺癌干细胞的可塑性
影响因子：
16.6
作者：
Chen, Wan-Jiun;Ho, Chao-Chi;Yang, Pan-Chyr
通讯作者：
Yang, Pan-Chyr