Lobb Richard J, van Amerongen Rosa, Wiegmans Adrian, Ham Sunyoung, Larsen Jill E, Möller Andreas
Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
School of Medicine, University of Queensland, Brisbane, QLD, 4072, Australia.
Int J Cancer. 2017 Aug 1;141(3):614-620. doi: 10.1002/ijc.30752. Epub 2017 May 12.
Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes.
非小细胞肺癌（NSCLC）是最常见的肺癌类型，也是肺癌患者最常见的死亡原因。NSCLC通常与化疗耐药相关，并且伴随着快速的转移扩散，导致治疗选择有限且患者生存率低。NSCLC具有异质性，由上皮性和间充质性NSCLC细胞组成。间充质性NSCLC细胞被认为是化疗耐药表型的原因，但这种表型能否以及如何转移到其他NSCLC细胞目前尚不清楚。我们假设间充质性NSCLC细胞分泌的小细胞外囊泡（外泌体）可能会将化疗耐药表型转移到周围的上皮性NSCLC细胞。为了探索这种可能性，我们使用了一种独特的人支气管上皮细胞（HBEC）模型，其中通过引入NSCLC中常见的致癌改变，将亲代细胞从上皮表型转变为间充质表型。我们发现，源自致癌转化的间充质性HBEC的外泌体可以将化疗耐药性转移给亲代上皮性HBEC，并增加受体细胞中一种主要的EMT转录因子ZEB1的mRNA水平。此外，我们证明间充质性而非上皮性HBEC的外泌体含有ZEB1 mRNA,从而为受体细胞中间充质表型的诱导提供了一种潜在机制。总之，这项工作首次证明源自间充质性、致癌转化的肺细胞的外泌体可以将化疗耐药性和间充质表型转移给受体细胞，可能是通过外泌体中ZEB1 mRNA的转移来实现的。
