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Long-term pulmonary exposure to multi-walled carbon nanotubes promotes breast cancer metastatic cascades


Anthropogenic carbon nanotubes, with a fibrous structure and physical properties similar to asbestos, have recently been found within human lung tissues. However, the reported carbon-nanotube-elicited pulmonary pathologies have been mostly confined to inflammatory or neoplastic lesions in the lungs or adjacent tissues. In the present study, we demonstrate that a single pulmonary exposure to multi-walled carbon nanotubes dramatically enhances angiogenesis and the invasiveness of orthotopically implanted mammary carcinoma, leading to metastasis and rapid colonization of the lungs and other organs. Exposure to multi-walled carbon nanotubes stimulates local and systemic inflammation, contributing to the formation of pre-metastatic and metastatic niches. Our study suggests that nanoscale-material-elicited pulmonary lesions may exert complex and extended influences on tumour progression. Given the increasing presence of carbon nanotubes in the environment, this report emphasizes the urgent need to escalate efforts assessing the long-term risks of airborne nanomaterial exposure in non-lung cancer progression.

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Fig. 1: Materials and experimental design.
Fig. 2: Pulmonary inflammation and fibrosis formation at day 120 after a single intratracheal instillation of MWCNTs.
Fig. 3: Assessment of primary breast tumours.
Fig. 4: Invasiveness of primary tumour cells derived from tumours in vivo.
Fig. 5: Evaluation of lung metastases of tumours.
Fig. 6: Positive feedback loop between VEGFA and COX-2 promotes cell invasion and metastasis.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.


  1. Tran, P. A., Zhang, L. & Webster, T. J. Carbon nanofibers and carbon nanotubes in regenerative medicine. Adv. Drug Deliv. Rev. 61, 1097–1114 (2009).

    Article  CAS  Google Scholar 

  2. Lee, S. W. et al. High-power lithium batteries from functionalized carbon-nanotube electrodes. Nat. Nanotechnol. 5, 531–537 (2010).

    Article  CAS  Google Scholar 

  3. Cha, C., Shin, S. R., Annabi, N., Dokmeci, M. R. & Khademhosseini, A. Carbon-based nanomaterials: multifunctional materials for biomedical engineering. ACS Nano 7, 2891–2897 (2013).

    Article  CAS  Google Scholar 

  4. De Volder, M. F., Tawfick, S. H., Baughman, R. H. & Hart, A. J. Carbon nanotubes: present and future commercial applications. Science 339, 535–539 (2013).

    Article  Google Scholar 

  5. Lee, J. H. et al. Exposure assessment of carbon nanotube manufacturing workplaces. Inhal. Toxicol. 22, 369–381 (2010).

    Article  CAS  Google Scholar 

  6. Howard, J. Current Intelligence Bulletin 65: Occupational Exposure to Carbon Nanotubes and Nanofibers (DHHS (NIOSH), 2013).

  7. Poland, C. A. et al. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat. Nanotechnol. 3, 423–428 (2008).

    Article  CAS  Google Scholar 

  8. Ryman-Rasmussen, J. P. et al. Inhaled carbon nanotubes reach the subpleural tissue in mice. Nat. Nanotechnol. 4, 747–751 (2009).

    Article  CAS  Google Scholar 

  9. Wang, P. et al. Multiwall carbon nanotubes mediate macrophage activation and promote pulmonary fibrosis through TGF-beta/Smad signaling pathway. Small 9, 3799–3811 (2013).

    Article  CAS  Google Scholar 

  10. Guarnieri, M. & Balmes, J. R. Outdoor air pollution and asthma. Lancet 383, 1581–1592 (2014).

    Article  CAS  Google Scholar 

  11. Liu, Y., Zhao, Y., Sun, B. & Chen, C. Understanding the toxicity of carbon nanotubes. Acc. Chem. Res. 46, 702–713 (2013).

    Article  CAS  Google Scholar 

  12. Wang, L. et al. Carbon nanotubes induce malignant transformation and tumorigenesis of human lung epithelial cells. Nano Lett. 11, 2796–2803 (2011).

    Article  CAS  Google Scholar 

  13. Shvedova, A. A. et al. MDSC and TGFβ are required for facilitation of tumor growth in the lungs of mice exposed to carbon nanotubes. Cancer Res. 75, 1615–1623 (2015).

    Article  CAS  Google Scholar 

  14. Luanpitpong, S. et al. Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity. Sci. Rep. 6, 39558–39572 (2016).

    Article  CAS  Google Scholar 

  15. Zheng, L. et al. Cardiovascular effects of pulmonary exposure to single-wall carbon nanotubes. Environ. Health Perspect. 115, 377–382 (2007).

    Article  Google Scholar 

  16. Suzui, M. et al. Multiwalled carbon nanotubes intratracheally instilled into the rat lung induce development of pleural malignant mesothelioma and lung tumors. Cancer Sci. 107, 924–935 (2016).

    Article  CAS  Google Scholar 

  17. Luanpitpong, S., Wang, L., Davidson, D. C., Riedel, H. & Rojanasakul, Y. Carcinogenic potential of high aspect ratio carbon nanomaterials. Environ. Sci. Nano 3, 483–493 (2016).

    Article  CAS  Google Scholar 

  18. Xu, J. et al. Multi-walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats. Cancer Sci. 103, 2045–2050 (2012).

    Article  CAS  Google Scholar 

  19. Donaldson, K. & Poland, C. A. Nanotoxicology: new insights into nanotubes. Nat. Nanotechnol. 4, 708–710 (2009).

    Article  CAS  Google Scholar 

  20. Kuhn, C. 3rd et al. An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am. Rev. Respir. Dis. 140, 1693–1703 (1989).

    Article  Google Scholar 

  21. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  22. Yilmaz, M., Christofori, G. & Lehembre, F. Distinct mechanisms of tumor invasion and metastasis. Trends Mol. Med. 13, 535–541 (2007).

    Article  CAS  Google Scholar 

  23. Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).

    Article  CAS  Google Scholar 

  24. Charafe-Jauffret, E. et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 69, 1302–1313 (2009).

    Article  CAS  Google Scholar 

  25. Liu, S. et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2, 78–91 (2014).

    Article  CAS  Google Scholar 

  26. Kitamura, T., Qian, B.-Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).

    Article  CAS  Google Scholar 

  27. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).

    Article  CAS  Google Scholar 

  28. Kusters, B. et al. Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis. Oncogene 26, 5808–5815 (2007).

    Article  CAS  Google Scholar 

  29. Hu, J. et al. Vascular endothelial growth factor promotes the expression of cyclooxygenase 2 and matrix metalloproteinases in Lewis lung carcinoma cells. Exp. Ther. Med. 4, 1045–1050 (2012).

    Article  CAS  Google Scholar 

  30. Greenhough, A. et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30, 377–386 (2009).

    Article  CAS  Google Scholar 

  31. Hugo, H. J., Saunders, C., Ramsay, R. G. & Thompson, E. W. New insights on COX-2 in chronic inflammation driving breast cancer growth and metastasis. J. Mammary Gland Biol. Neoplasia 20, 109–119 (2015).

    Article  Google Scholar 

  32. Nikota, J. et al. Stat-6 signaling pathway and not interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part. Fibre Toxicol. 14, 37–57 (2017).

    Article  Google Scholar 

  33. Wilczynski, J. R. & Duechler, M. How do tumors actively escape from host immunosurveillance? Arch. Immunol. Ther. Exp. ( Warsz. ) 58, 435–448 (2010).

    Article  CAS  Google Scholar 

  34. Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15–18 (2002).

    Article  CAS  Google Scholar 

  35. Bielenberg, D. R. & Zetter, B. R. The contribution of angiogenesis to the process of metastasis. Cancer J. 21, 267–273 (2015).

    Article  CAS  Google Scholar 

  36. Wu, M. et al. Case report. Lung disease in World Trade Center responders exposed to dust and smoke: carbon nanotubes found in the lungs of World Trade Center patients and dust samples. Environ. Health Perspect. 118, 499–504 (2010).

    Article  CAS  Google Scholar 

  37. Kolosnjaj-Tabi, J. et al. Anthropogenic carbon nanotubes found in the airways of Parisian children. EBioMedicine 2, 1697–1704 (2015).

    Article  Google Scholar 

  38. Oberdorster, G., Castranova, V., Asgharian, B. & Sayre, P. Inhalation exposure to carbon nanotubes (CNT) and carbon nanofibers (CNF): methodology and dosimetry. J. Toxicol. Environ. Health B Crit. Rev. 18, 121–212 (2015).

    Article  CAS  Google Scholar 

  39. Liu, Y. et al. Gd-metallofullerenol nanomaterial as non-toxic breast cancer stem cell-specific inhibitor. Nat. Commun. 6, 5988–6005 (2015).

    Article  CAS  Google Scholar 

  40. Park, E. K. et al. Optimized THP-1 differentiation is required for the detection of responses to weak stimuli. Inflamm. Res. 56, 45–50 (2007).

    Article  CAS  Google Scholar 

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This work was supported by the National Key R&D Program of China (2016YFC1302305, 2016YFA0201600, 2016YFE0133100), the National Natural Science Foundation of China (81672615, 815022829, 91543206, 31622026, 31700879), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (11621505), the Shenzhen Development and Reform Commission Subject Construction Project [2017]1434, the Bureau of International Co-operation Chinese Academy of Sciences (GJHG1852) and the National Science Fund for Distinguished Young Scholars (11425520).

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Authors and Affiliations



T.Z. and C.C. conceived the project and supervised the study. T.Z., C.C., X.L. and Y.Z. designed the experiments. X.L. and Y.Z. performed experiments with assistance from R.B., Z.W., W.Q., L.Y., R.C., H.Y., Y.L., T.L. and V.P.; X.L. and Y.Z. analysed the data. T.Z., C.C. and X.L. co-wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Chunying Chen or Tao Zhu.

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The authors declare no competing interests.

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Journal peer review information: Nature Nanotechnology thanks Wolfgang Kreyling, Iseult Lynch and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Lu, X., Zhu, Y., Bai, R. et al. Long-term pulmonary exposure to multi-walled carbon nanotubes promotes breast cancer metastatic cascades. Nat. Nanotechnol. 14, 719–727 (2019).

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