Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis

Our plain-English summary of Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis, by S. Luanpitpong, L. Wang, T.A. Stueckle, et al (Oncotarget, 2014).

The study

• Authors: S. Luanpitpong, L. Wang, T.A. Stueckle, W. Tse, Y.C. Chen, Y. Rojanasakul
• Journal: Oncotarget
• Published: 2014;5(11):3541-54
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cancer stem cells (CSCs) may represent targets for carcinogenic initiation by chemical and environmental agents. Recent studies have raised a concern over the potential carcinogenicity of carbon nanotubes (CNTs), one of the most commonly used engineered nanomaterials with asbestos-like properties. Here, we show that chronic (6-month) exposure of human lung epithelial cells to single-walled (SW) CNTs at the workplace-relevant concentration induced an emergence of lung CSCs, as indicated by the induction of CSC tumor spheres and side population (SP). These CSCs, which were found to overexpress tumor promoter caveolin-1 (Cav-1), displayed aggressive cancer phenotypes of apoptosis resistance and enhanced cell invasion and migration compared with their non-CSC counterpart. Using gene manipulation strategies, we reveal for the first time that Cav-1 plays an essential role in CSC regulation and aggressiveness of SWCNT-transformed cells partly through p53 dysregulation, consistent with their suggested role by microarray and gene ontology analysis. Cav-1 not only promoted tumorigenesis in a xenograft mouse model but also metastasis of the transformed cells to neighboring tissues. Since CSCs are crucial to the initiation and early development of carcinogenesis, our findings on CSC induction by SWCNTs and Cav-1 could aid in the early detection and risk assessment of the disease.

In plain English

This was a laboratory study of single-walled carbon nanotubes (SWCNTs), which the authors describe as sharing properties with asbestos fibers. Non-tumorigenic human lung epithelial BEAS-2B cells were exposed continuously to a non-cytotoxic SWCNT dose of 0.02 micrograms per square centimetre for 6 months (designated BSW cells) and compared with passage-matched unexposed control cells (BC). The exposed cells formed soft-agar colonies and floating tumour spheres, and their side population (SP, a cancer stem-like cell marker) was higher than in controls (about 15% versus 3%), with high CD133 and ABCG2 expression. Sorted SP cells formed more spheres and colonies, migrated and invaded more, resisted TNF-alpha-induced apoptosis, and produced more tumours in NSG mice than non-SP cells. Microarray analysis found 1932 differentially expressed genes (693 up, 1239 down), with CAV1 increased about 2.5-fold. Caveolin-1 overexpression increased the side population and tumour growth in mice and lowered p53; Cav-1 knockdown raised p53. The authors concluded SWCNTs can induce cancer stem-like cells and that Cav-1 positively regulates this process.

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: Laboratory experimental study: chronic in vitro exposure of human lung epithelial cells, gene manipulation, microarray analysis, and mouse xenograft experiments
• Who was studied: Human bronchial epithelial BEAS-2B cells (exposed BSW and passage-matched control BC), non-small cell lung cancer H460 cells as positive control, and immunodeficient NOD/SCID gamma (NSG) mice used for xenografts
• Exposure: Purified single-walled carbon nanotubes (99% elemental carbon, 0.23% iron by weight), 0.02 micrograms per square centimetre continuously for 6 months (described as workplace-relevant); separate acute doses of 0 to 0.15 micrograms per square centimetre for reactive oxygen species measurement
• Main results:
  • The side population fraction was higher in chronically SWCNT-exposed BSW cells than in control BC cells (about 15% versus 3%), comparable to H460 lung cancer cells
  • CD133 was expressed in BSW and H460 cells but not in control BC cells, and ABCG2 was upregulated in BSW cells
  • Sorted SP cells from BSW cells formed more and larger spheres and soft agar colonies than non-SP cells, and had greater tumour incidence, size and volume in xenografted mice
  • SP cells showed significantly greater migration and invasion than NSP cells, and less apoptosis after TNF-alpha (150 ng/mL)
  • Microarray comparison of BSW with BC cells identified 1932 differentially expressed genes (693 upregulated, 1239 downregulated) at fold change of at least 2 and p of 0.05 or less; CAV1 was increased approximately 2.5-fold in BSW cells
  • p53 protein was lowest and Cav-1 highest in SP cells (p53 rank BC > NSP > SP; Cav-1 rank SP > NSP > BC)
  • In transfected BSW cells, p53 overexpression reduced the side population and tumour spheres and reduced migration, while Cav-1 overexpression increased them
  • Cav-1 overexpression decreased p53 expression and Cav-1 shRNA knockdown increased it in BSW cells
  • In NSG mice injected with 3x10^5 luciferase-labelled cells per flank, tumour signals were significantly higher for Cav-1-overexpressing cells at 3 and 4 weeks, with a maximum of about 4-fold tumour induction over control cells, and metastatic cells were seen in neighbouring muscle tissue
  • SWCNTs (0 to 0.15 micrograms per square centimetre) produced dose- and time-dependent increases in DCF fluorescence in BC cells, inhibited by N-acetylcysteine (5 mM)
• The authors' conclusion: The authors concluded that SWCNTs can induce cancer stem-like cells and tumorigenesis in a xenograft mouse model, and that Cav-1, acting upstream of p53, positively regulates this tumorigenic process and might aid early detection of CNT-induced lung carcinogenesis

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, STEM, Tumorigenesis, Carcinogenic, Apoptosis, Metastasis, Carcinogenesis.

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)
• Role of p53 in the chronic pulmonary immune response to tangled or rod-like multi-walled carbon nanotubes — K.S. Duke, E.A. Thompson, et al. (2018)
• Role of mesothelin in carbon nanotube-induced carcinogenic transformation of human bronchial epithelial cells — X. He, E. Despeaux, et al. (2016)
• Multipotent cancer stem cells derived from human malignant peritoneal mesothelioma promote tumorigenesis — S. Varghese, R. Whipple, et al. (2012)
• Identification of cancer stem cell markers in human malignant mesothelioma cells — F.I. Ghani, H. Yamazaki, et al. (2011)
• Induction and recovery of CpG site specific methylation changes in human bronchial cells after long-term exposure to carbon nanotubes and asbestos — D. Öner, M. Ghosh, et al. (2020)

Browse more research in Oncotarget, or return to medical research.