Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation.
Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation.
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DOI：
10.1038/cddis.2014.136
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发表时间：
2014-04-10
影响因子：
9
通讯作者：
Pass HI
中科院分区：
文献类型：
--
作者：
Cioce M;Canino C;Goparaju C;Yang H;Carbone M;Pass HI
恶性胸膜间皮瘤（MPM）的临床管理是非常具有挑战性的，因为这种肿瘤对化疗的罕见耐药性。我们在这里报告增加巨噬细胞集落刺激因子-1-受体（M-CSF/CSF-1 R）mRNA的表达在间皮瘤与正常组织标本，并证明CSF-1 R的表达识别化疗耐药细胞的间皮瘤性质的原代培养和间皮瘤细胞系。通过使用RNAi或配体捕获，我们证明了这些细胞的化学抗性特性取决于自分泌CSF-1 R信号传导。在单细胞水平，分离的CSF-1 Rpos细胞表现出多能性、上皮-间充质转化和解毒因子的复杂库，其定义了克隆形成、化学抗性、趋化因子样细胞亚群。在未转化的间皮瘤细胞中，CSF-1 R的简单激活足以赋予间皮瘤的标志--集落形成性和对培美曲塞的耐药性。此外，这诱导了高度模拟在内源性表达受体和配体的MPM细胞中观察到的基因表达谱，表明CSF-1 R表达主要负责鉴定的细胞亚群的表型。CSF 1 Rpos细胞的存活需要活跃的AKT（v-akt鼠胸腺瘤病毒癌基因同源物1）信号传导，这有助于细胞核转录活性β-连环蛋白水平的增加。在培美曲塞处理后，抑制AKT降低了β-连环蛋白依赖性报告基因的转录活性，并使细胞对衰老诱导的克隆性死亡敏感。这项工作扩展了CSF-1 R的非巨噬细胞功能及其在实体瘤中的作用，并表明CSF-1 R信号可能在原型炎症相关癌症（如MPM）中具有关键的致病作用，因此可能是治疗干预的有希望的靶点。
Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1Rpos cells exhibit a complex repertoire of pluripotency, epithelial–mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1Rpos cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention.