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

Article metrics

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 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).

  2. 2.

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

  3. 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).

  4. 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).

  5. 5.

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

  6. 6.

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

  7. 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).

  8. 8.

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

  9. 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).

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 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).

  14. 14.

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

  15. 15.

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

  16. 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).

  17. 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).

  18. 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).

  19. 19.

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

  20. 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).

  21. 21.

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

  22. 22.

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

  23. 23.

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

  24. 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).

  25. 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).

  26. 26.

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

  27. 27.

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

  28. 28.

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

  29. 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).

  30. 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).

  31. 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).

  32. 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).

  33. 33.

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

  34. 34.

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

  35. 35.

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

  36. 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).

  37. 37.

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

  38. 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).

  39. 39.

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

  40. 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).

Download references

Acknowledgements

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).

Author information

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.

Correspondence to Chunying Chen or Tao Zhu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–19, Supplementary Table 1–5

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading