EMT and Acquisition of Stem Cell-Like Properties Are Involved in Spontaneous Formation of Tumorigenic Hybrids between Lung Cancer and Bone Marrow-Derived Mesenchymal Stem Cells
EMT and Acquisition of Stem Cell-Like Properties Are Involved in Spontaneous Formation of Tumorigenic Hybrids between Lung Cancer and Bone Marrow-Derived Mesenchymal Stem Cells
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EMT 和干细胞样特性的获得参与肺癌和骨髓间充质干细胞之间致瘤杂交体的自发形成
DOI：
10.1371/journal.pone.0087893
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发表时间：
2014-02-06
期刊：
影响因子：
3.7
通讯作者：
Liu, Guo-Xiang
中科院分区：
文献类型：
--
作者：
Xu, Mei-Hua;Gao, Xuan;Liu, Guo-Xiang
癌症进展中最致命的阶段是转移性转化。上皮-间质转化（EMT）是癌细胞获得侵袭性和转移性表型的关键过程。为了产生肉眼可见的转移，播散的癌细胞似乎需要自我更新能力。然而，定义这些过程的基本机制知之甚少。转移的一个可能机制是骨髓细胞和癌细胞之间的融合。在这项研究中，我们发现骨髓间充质干细胞（MSC）和三种不同的非小细胞肺癌（NSCLC）细胞系之间自发形成的致瘤性杂交瘤导致了具有EMT和干细胞样特性的高度恶性亚群。杂交细胞失去了上皮形态，呈现成纤维细胞样外观。在致瘤杂交瘤中观察到波形蛋白、α-平滑肌肌动蛋白（α-SMA）和纤连蛋白的上调，以及E-钙粘蛋白和泛细胞角蛋白的下调。这些细胞还表现出干细胞标志物CD 133的表达增加以及转录因子OCT 4、Nanog、BMI 1、Notch 1、ALDH 1以及Sox 2的过表达，所有这些基因都负责调节和维持干细胞表型。此外，在自发形成的致瘤性杂交瘤中，NOD/SCID小鼠中可检测到增加的气囊形成能力和肿瘤形成能力。因此，肺癌细胞和间充质干细胞之间的细胞融合提供了一种非突变机制，这种机制可能导致异常的基因表达模式，并产生高度恶性的亚群，既能够进行EMT，又具有癌症干细胞（CSC）的特性。
The most deadly phase in cancer progression is metastatic conversion. Epithelial-to-mesenchymal transition (EMT) is a key process by which cancer cells acquire invasive and metastatic phenotypes. In order to spawn macroscopic metastases, disseminated cancer cells would seem to require self-renewal capability. However, the underlying mechanism defining these processes is poorly understood. One possible mechanism underlying metastasis is fusion between myeloid cells and cancer cells. In this study, we found that spontaneously-formed tumorigenic hybrids between bone marrow-derived mesenchymal stem cells (MSCs) and three different non-small cell lung cancer (NSCLC) cell lines contributed to highly malignant subpopulations with both EMT and stem cell-like properties. Hybrids lost their epithelial morphology and assumed a fibroblast-like appearance. Up-regulation of vimentin, α-smooth muscle actin (α-SMA), and fibronectin, and down-regulation of E-cadherin and pancytokeratin were observed in tumorigenic hybrids. These cells also exhibited increased expression of the stem cell marker prominin-1 (CD133) and over-expression of transcription factors OCT4, Nanog, BMI1, Notch1, ALDH1 as well as Sox2, all genes responsible for regulating and maintaining the stem cell phenotype. In addition, in spontaneously-formed tumorigenic hybrids, increased pneumosphere-forming capacity and tumor-forming ability in NOD/SCID mice were detectable. Thus, cell fusion between lung cancer cells and MSCs provides a nonmutational mechanism that could contribute to aberrant gene expression patterns and give rise to highly malignant subpopulations both capable of EMT and with properties of cancer stem cells (CSCs).