Format

Send to

Choose Destination
Curr Biol. 2017 Nov 6;27(21):3302-3314.e6. doi: 10.1016/j.cub.2017.09.007.

Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf).

Author information

1
Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
2
Medical Research Council/University of Edinburgh, Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
3
Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK; University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK.
4
University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK.
5
Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
6
Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK. Electronic address: mb446@le.ac.uk.
7
Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK. Electronic address: aew5@le.ac.uk.
8
Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK. Electronic address: mm21@le.ac.uk.

Abstract

Mesothelioma is a fatal tumor of the pleura and is strongly associated with asbestos exposure. The molecular mechanisms underlying the long latency period of mesothelioma and driving carcinogenesis are unknown. Moreover, late diagnosis means that mesothelioma research is commonly focused on end-stage disease. Although disruption of the CDKN2A (INK4A/ARF) locus has been reported in end-stage disease, information is lacking on the status of this key tumor suppressor gene in pleural lesions preceding mesothelioma. Manufactured carbon nanotubes (CNTs) are similar to asbestos in terms of their fibrous shape and biopersistent properties and thus may pose an asbestos-like inhalation hazard. Here we show that instillation of either long CNTs or long asbestos fibers into the pleural cavity of mice induces mesothelioma that exhibits common key pro-oncogenic molecular events throughout the latency period of disease progression. Sustained activation of pro-oncogenic signaling pathways, increased proliferation, and oxidative DNA damage form a common molecular signature of long-CNT- and long-asbestos-fiber-induced pathology. We show that hypermethylation of p16/Ink4a and p19/Arf in CNT- and asbestos-induced inflammatory lesions precedes mesothelioma; this results in silencing of Cdkn2a (Ink4a/Arf) and loss of p16 and p19 protein, consistent with epigenetic alterations playing a gatekeeper role in cancer. In end-stage mesothelioma, silencing of p16/Ink4a is sustained and deletion of p19/Arf is detected, recapitulating human disease. This study addresses the long-standing question of which early molecular changes drive carcinogenesis during the long latency period of mesothelioma development and shows that CNT and asbestos pose a similar health hazard.

KEYWORDS:

CDKN2A; asbestos; carbon nanotubes; epigenetics; hypermethylation; mesothelioma; toxicity; tumor suppressor genes

PMID:
29112861
PMCID:
PMC5681354
DOI:
10.1016/j.cub.2017.09.007
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center