Induction of stem-like cells with malignant properties by chronic exposure of human lung epithelial cells to single-walled carbon nanotubes.
Induction of stem-like cells with malignant properties by chronic exposure of human lung epithelial cells to single-walled carbon nanotubes.
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DOI：
10.1186/1743-8977-11-22
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发表时间：
2014-05-11
影响因子：
10
通讯作者：
Rojanasakul Y
中科院分区：
文献类型：
--
作者：
Luanpitpong S;Wang L;Castranova V;Rojanasakul Y
碳纳米管（CNT）有望为商业和生物医学应用创造新的更好的产品，但其长期的不良健康影响是一个主要问题。本研究的目的是通过对导致致癌作用的细胞和分子过程的基本理解，解决与慢性肺暴露于单壁（SW）CNT相关的人类肺癌风险。我们假设，获得癌症干细胞（CSC），一个亚群，驱动肿瘤的起始和进展，可能有助于CNT致癌。将非致瘤性人肺上皮细胞长期暴露于充分分散的SWCNT 6个月，生理相关浓度为0.02 μg/cm 2表面积剂量。在肿瘤球和侧群（SP）的CSC选择性条件下，评价慢性SWCNT暴露的细胞中CSC样细胞的存在。使用荧光激活细胞分选分离CSC样细胞，并评估其侵袭性行为，包括获得性凋亡抗性和体外细胞迁移和侵袭增加，以及体内肿瘤引发能力。非小细胞肺癌细胞作为阳性对照。我们首次证明了慢性SWCNT暴露的肺上皮细胞的所有克隆中存在CSC样细胞。这些CSC样细胞，与它们的非CSC对应物相反，具有肺CSC的所有生物学特征，这些生物学特征是不可逆恶性转化、自我更新、侵袭性癌症行为和体内肿瘤发生的核心。这些细胞还显示出异常的干细胞标志物，特别是Nanog、SOX-2、SOX-17和E-钙粘蛋白。肿瘤抑制因子p53的恢复表达废除了CSC样细胞的CSC特性。此外，我们确定了与SWCNT诱导的CSC形成和肿瘤发生相关的特异性干细胞表面标志物CD 24 low和CD 133 high。我们的研究结果为慢性单壁碳纳米管暴露诱导的CSC样细胞的获得提供了新的和令人信服的证据，这可能是单壁碳纳米管肿瘤发生的主要驱动力。因此，我们的研究支持谨慎采取预防策略和实施暴露控制的SWCNT。我们还建议，CSC和相关的表面标志物的检测可能提供一个有效的筛选工具，预测单壁碳纳米管和相关纳米颗粒的致癌潜力。
Carbon nanotubes (CNT) hold great promise to create new and better products for commercial and biomedical applications, but their long-term adverse health effects are a major concern. The objective of this study was to address human lung cancer risks associated with chronic pulmonary exposure to single-walled (SW) CNT through the fundamental understanding of cellular and molecular processes leading to carcinogenesis. We hypothesized that the acquisition of cancer stem cells (CSC), a subpopulation that drive tumor initiation and progression, may contribute to CNT carcinogenesis. Non-tumorigenic human lung epithelial cells were chronically exposed to well-dispersed SWCNT for a period of 6 months at the physiologically relevant concentration of 0.02 μg/cm2 surface area dose. Chronic SWCNT-exposed cells were evaluated for the presence of CSC-like cells under CSC-selective conditions of tumor spheres and side population (SP). CSC-like cells were isolated using fluorescence-activated cell sorting and were assessed for aggressive behaviors, including acquired apoptosis resistance and increased cell migration and invasion in vitro, and tumor-initiating capability in vivo. Non-small cell lung cancer cells served as a positive control. We demonstrated for the first time the existence of CSC-like cells in all clones of chronic SWCNT-exposed lung epithelial cells. These CSC-like cells, in contrary to their non-CSC counterpart, possessed all biological features of lung CSC that are central to irreversible malignant transformation, self-renewal, aggressive cancer behaviors, and in vivo tumorigenesis. These cells also displayed aberrant stem cell markers, notably Nanog, SOX-2, SOX-17 and E-cadherin. Restored expression of tumor suppressor p53 abrogated CSC properties of CSC-like cells. Furthermore, we identified specific stem cell surface markers CD24low and CD133high that are associated with SWCNT-induced CSC formation and tumorigenesis. Our findings provide new and compelling evidence for the acquisition of CSC-like cells induced by chronic SWCNT exposure, which are likely to be a major driving force for SWCNT tumorigenesis. Thus, our study supports prudent adoption of prevention strategies and implementation of exposure control for SWCNT. We also suggest that the detection of CSC and associated surface markers may provide an effective screening tool for prediction of the carcinogenic potential of SWCNT and related nanoparticles.
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作者：
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通讯作者：
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通讯作者：
Tang, D. G.