Chan Ryan, Sethi Pallavi, Jyoti Amar, McGarry Ronald, Upreti Meenakshi
a Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536-0596; and b Department of Radiation Medicine, University of Kentucky Albert B. Chandler Hospital, Lexington, Kentucky 40536-0293.
Radiat Res. 2016 Feb;185(2):169-81. doi: 10.1667/RR14285.1. Epub 2016 Feb 2.
Lung cancer is the most common cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer. While recent research has shown that cancer stem cells (CSC) exhibit radioresistant and chemoresistant properties, current cancer therapy targets the bulk of the tumor burden without accounting for the CSC and the contribution of the tumor microenvironment. CSC interaction with the stroma enhances NSCLC survival, thus limiting the efficacy of treatment. The aim of this study was to elucidate the role of CSC and the microenvironment in conferring radio- or chemoresistance in an in vitro tumor model for NSCLC. The novel in vitro three-dimensional (3D) NSCLC model of color-coded tumor tissue analogs (TTA) that we have developed is comprised of human lung adenocarcinoma cells, fibroblasts, endothelial cells and NSCLC cancer stem cells maintained in low oxygen conditions (5% O2) to recapitulate the physiologic conditions in tumors. Using this model, we demonstrate that a single 5 Gy radiation dose does not inhibit growth of TTA containing CSC and results in elevated expression of cytokines (TGF-α, RANTES, ENA-78) and factors (vimentin, MMP and TIMP), indicative of an invasive and aggressive phenotype. However, combined treatment of single dose or fractionated doses with cisplatin was found to either attenuate or decrease the proliferative effect that radiation exposure alone had on TTA containing CSC maintained in hypoxic conditions. In summary, we utilized a 3D NSCLC model, which had characteristics of the tumor microenvironment and tumor cell heterogeneity, to elucidate the multifactorial nature of radioresistance in tumors.
肺癌是全球癌症相关死亡的最常见原因，非小细胞肺癌（NSCLC）占所有肺癌的约85%。虽然最近的研究表明癌症干细胞（CSC）具有抗辐射和抗化学特性，但目前的癌症治疗针对的是大部分肿瘤负荷，而没有考虑到CSC和肿瘤微环境的作用。CSC与基质的相互作用增强了NSCLC的存活率，从而限制了治疗效果。本研究的目的是在NSCLC的体外肿瘤模型中阐明CSC和微环境在赋予放射抗性或化学抗性方面的作用。我们开发的新型体外三维（3D）NSCLC模型，即颜色编码肿瘤组织类似物（TTA），由人肺腺癌细胞、成纤维细胞、内皮细胞和NSCLC癌症干细胞组成，在低氧条件（5% O2）下维持，以重现肿瘤中的生理条件。使用该模型，我们证明单次5 Gy辐射剂量不会抑制含有CSC的TTA的生长，并导致细胞因子（TGF-α、RANTES、ENA-78）和因子（波形蛋白、MMP和TIMP）的表达升高，这表明具有侵袭性和侵袭性表型。然而，发现顺铂单剂量或分次剂量的联合治疗可减弱或降低单独辐射暴露对低氧条件下含有CSC的TTA的增殖作用。总之，我们利用了一个具有肿瘤微环境和肿瘤细胞异质性特征的3D NSCLC模型，来阐明肿瘤中放射抗性的多因素性质。
