Acquisition of Cancer Stem Cell-like Properties in Human Small Airway Epithelial Cells after a Long-term Exposure to Carbon Nanomaterials

Our plain-English summary of Acquisition of Cancer Stem Cell-like Properties in Human Small Airway Epithelial Cells after a Long-term Exposure to Carbon Nanomaterials, by C. Kiratipaiboon, T.A. Stueckle, R. Ghosh, et al (Environmental Science. Nano, 2019).

The study

• Authors: C. Kiratipaiboon, T.A. Stueckle, R. Ghosh, L.W. Rojanasakul, Y.C. Chen, C.Z. Dinu, Y. Rojanasakul
• Journal: Environmental Science. Nano
• Published: 2019;6(7):2152-2170
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cancer stem cells (CSCs) are a key driver of tumor formation and metastasis, but how they are affected by nanomaterials is largely unknown. The present study investigated the effects of different carbon-based nanomaterials (CNMs) on neoplastic and CSC-like transformation of human small airway epithelial cells and determined the underlying mechanisms. Using a physiologically relevant exposure model (long-term/low-dose) with system validation using a human carcinogen, asbestos, we demonstrated that single-walled carbon nanotubes, multi-walled carbon nanotubes, ultrafine carbon black, and crocidolite asbestos induced particle-specific anchorage-independent colony formation, DNA-strand break, and p53 downregulation, indicating genotoxicity and carcinogenic potential of CNMs. The chronic CNM-exposed cells exhibited CSC-like properties as indicated by 3D spheroid formation, anoikis resistance, and CSC markers expression. Mechanistic studies revealed specific self-renewal and epithelial-mesenchymal transition (EMT)-related transcription factors that are involved in the cellular transformation process. Pathway analysis of gene signaling networks supports the role of SOX2 and SNAI1 signaling in CNM-mediated transformation. These findings support the potential carcinogenicity of high aspect ratio CNMs and identified molecular targets and signaling pathways that may contribute to the disease development.

In plain English

This was an in vitro laboratory study in which immortalized human small airway epithelial cells (SAECs) were continuously exposed for 6 months to a low, non-cytotoxic dose (0.02 micrograms per square centimetre) of single-walled carbon nanotubes (SWCNT), multi-walled carbon nanotubes (MWCNT), ultrafine carbon black (UFCB), or crocidolite asbestos, the asbestos serving as a carcinogenic particle control with a fibre shape similar to carbon nanotubes. Compared with passage-matched control cells, exposed cells formed more and larger colonies in soft agar (most for asbestos- and SWCNT-exposed cells), showed more cells with more than 5 gamma-H2AX foci (a marker of DNA double-strand breaks), had reduced p53 protein, resisted detachment-induced death, formed more primary and secondary spheroids, and expressed more of the stem-cell marker CD133. SOX2 protein rose 15-fold in SWCNT-, 2.5-fold in MWCNT- and 16-fold in asbestos-exposed cells, while SNAI1 rose in SWCNT-, MWCNT- and UFCB-exposed cells but fell in asbestos-exposed cells. The authors concluded these findings support potential carcinogenicity of high aspect ratio carbon nanomaterials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro long-term, low-dose exposure experiment in cultured human lung epithelial cells, with crocidolite asbestos as a carcinogen control, plus pathway analysis of previously published microarray data
• Who was studied: Primary human small airway epithelial cells immortalized with hTERT (SAECs), cultured and exposed for 6 months; no human subjects
• Exposure: Continuous culture exposure to 0.02 micrograms per square centimetre of SWCNT, MWCNT (MWNT-7), UFCB (Elftex 12) or crocidolite asbestos for 6 months; asbestos contained 50.9% SiO2, 31.8% iron, less than 1% carbon
• Main results:
  • Asbestos- and SWCNT-exposed cells formed the most soft-agar colonies, then MWCNT- and UFCB-exposed cells, while control cells formed very few small colonies
  • All four particle-exposed cell groups, including asbestos, showed significantly more gamma-H2AX-positive cells (more than 5 foci per cell) than control cells; SWCNT-exposed cells showed the most marked change
  • p53 protein was lower in SWCNT-, MWCNT-, UFCB- and asbestos-exposed cells than in controls, most markedly in SWCNT-exposed cells
  • Phospho-p53 expression remained intact in the exposed cells
  • Asbestos-, SWCNT- and MWCNT-exposed cells kept anoikis resistance from 9 to 60 hours after detachment; UFCB-exposed cells only at 9 to 12 hours
  • All particle-exposed groups formed significantly more primary spheroids than controls; secondary spheroids were highest for asbestos- and SWCNT-exposed cells
  • CD133 was significantly raised in secondary spheroids of all particle-exposed cells, highest in SWCNT-exposed, then asbestos- and MWCNT-exposed, lowest in UFCB-exposed
  • SOX2 protein increased 15-fold in SWCNT-exposed, 2.5-fold in MWCNT-exposed and 16-fold in asbestos-exposed cells over the control level
  • SNAI1 was highly upregulated in SWCNT-, MWCNT- and UFCB-exposed cells but downregulated in asbestos-exposed cells
  • In pathway analysis of asbestos-exposed cells, cancer was the top ranked cellular function, with 236 differentially expressed genes and a log p-value of 9.5 x 10 to the minus 6; SOX2 was found to activate CD44 and ETV5
• The authors' conclusion: The authors concluded that long-term low-dose exposure to carbon nanomaterials and asbestos caused DNA damage, p53 dysregulation and neoplastic and cancer stem cell-like properties in the cells, that high aspect ratio materials had stronger effects than low aspect ratio UFCB, and that SOX2 and SNAI1 may be key drivers of the transformation
• Limitations the authors state:
  • The authors stated that hydrodynamic size measurements of non-spherical particles such as carbon nanotubes and asbestos fibres are only estimates and should be treated with caution
  • The authors noted that studies of the long-term adverse effects of carbon nanomaterials are very limited

Topics

Medical terms in this study, explained in our Lexicon: STEM, Metastasis, Crocidolite, Genotoxicity, Carcinogenic, Aspect Ratio (Length-to-diameter ratio).

Related studies

• Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells — L. Wang, T.A. Stueckle, et al. (2014)
• Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis — S. Luanpitpong, L. Wang, et al. (2014)
• Dispersion medium modulates oxidative stress response of human lung epithelial cells upon exposure to carbon nanomaterial samples — E. Herzog, H.J. Byrne, et al. (2009)
• Long-term effects of carbon containing engineered nanomaterials and asbestos in the lung: one year postexposure comparisons — A.A. Shvedova, N. Yanamala, et al. (2014)
• Severe diffuse small airways abnormalities in long term chrysotile asbestos miners — J.L. Wright, A. Churg (1985)
• A comparison of acute and long-term effects of industrial multiwalled carbon nanotubes on human lung and immune cells in vitro — T. Thurnherr, C. Brandenberger, et al. (2011)

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