Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A non-genetic route to aneuploidy in human cancers

Nature Cell Biology volume 13, pages 324–330 (2011)Cite this article

Subjects

Abstract

Aneuploidy is common in human tumours and is often indicative of aggressive disease. Aneuploidy can result from cytokinesis failure, which produces binucleate cells that generate aneuploid offspring with subsequent divisions. In cancers, disruption of cytokinesis is known to result from genetic perturbations to mitotic pathways or checkpoints. Here we describe a non-genetic mechanism of cytokinesis failure that occurs as a direct result of cell-in-cell formation by entosis. Live cells internalized by entosis, which can persist through the cell cycle of host cells, disrupt formation of the contractile ring during host cell division. As a result, cytokinesis frequently fails, generating binucleate cells that produce aneuploid cell lineages. In human breast tumours, multinucleation is associated with cell-in-cell structures. These data define a previously unknown mechanism of cytokinesis failure and aneuploid cell formation that operates in human cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cell-in-cell structures are multinucleated.
Figure 2: Host cells fail cytokinesis.
Figure 3: Internalized cells disrupt the cleavage furrow.
Figure 4: Internalized cells block cleavage furrow formation.
Figure 5: Binucleated cell-in-cell structures generate aneuploid lineages.

Similar content being viewed by others

References

  1. Rajagopalan, H. & Lengauer, C. Aneuploidy and cancer. Nature 432, 338–341 (2004).

    Article  CAS  Google Scholar 

  2. Weaver, B. A. & Cleveland, D. W. Does aneuploidy cause cancer? Curr. Opin. Cell Biol. 18, 658–667 (2006).

    Article  CAS  Google Scholar 

  3. Pinto, A. E., Andre, S., Pereira, T., Silva, G. & Soares, J. DNA flow cytometry but not telomerase activity as predictor of disease-free survival in pT1-2/N0/G2 breast cancer. Pathobiology 73, 63–70 (2006).

    Article  CAS  Google Scholar 

  4. Araujo, S. E., Bernardo, W. M., Habr-Gama, A., Kiss, D. R. & Cecconello, I. DNA ploidy status and prognosis in colorectal cancer: a meta-analysis of published data. Dis. Colon Rectum 50, 1800–1810 (2007).

    Article  Google Scholar 

  5. Suehiro, Y. et al. Aneuploidy predicts outcome in patients with endometrial carcinoma and is related to lack of CDH13 hypermethylation. Clin. Cancer Res. 14, 3354–3361 (2008).

    Article  CAS  Google Scholar 

  6. Susini, T. et al. Ten-year results of a prospective study on the prognostic role of ploidy in endometrial carcinoma: DNA aneuploidy identifies high-risk cases among the so-called ‘low-risk’ patients with well and moderately differentiated tumors. Cancer 109, 882–890 (2007).

    Article  CAS  Google Scholar 

  7. Pinto, A. E., Monteiro, P., Silva, G., Ayres, J. V. & Soares, J. Prognostic biomarkers in renal cell carcinoma: relevance of DNA ploidy in predicting disease-related survival. Int. J. Biol. Markers 20, 249–256 (2005).

    Article  CAS  Google Scholar 

  8. Ganem, N. J., Godinho, S. A. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278–282 (2009).

    Article  CAS  Google Scholar 

  9. Ganem, N. J., Storchova, Z. & Pellman, D. Tetraploidy, aneuploidy and cancer. Curr. Opin. Genet. Dev. 17, 157–162 (2007).

    CAS  PubMed  Google Scholar 

  10. Boveri, T. The Origin of Malignant Tumors (Williams and Wilkins, 1929).

    Google Scholar 

  11. King, R. W. When 2+2=5: the origins and fates of aneuploid and tetraploid cells. Biochim. Biophys. Acta 1786, 4–14 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005).

    Article  CAS  Google Scholar 

  13. Nadler, Y. et al. Expression of Aurora A (but not Aurora B) is predictive of survival in breast cancer. Clin. Cancer Res. 14, 4455–4462 (2008).

    Article  CAS  Google Scholar 

  14. Wang, X. et al. Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 25, 7148–7158 (2006).

    Article  CAS  Google Scholar 

  15. Casenghi, M. et al. p53-independent apoptosis and p53-dependent block of DNA rereplication following mitotic spindle inhibition in human cells. Exp. Cell Res. 250, 339–350 (1999).

    Article  CAS  Google Scholar 

  16. Tsuiki, H. et al. Mechanism of hyperploid cell formation induced by microtubule inhibiting drug in glioma cell lines. Oncogene 20, 420–429 (2001).

    Article  CAS  Google Scholar 

  17. Minn, A. J., Boise, L. H. & Thompson, C. B. Expression of Bcl-xL and loss of p53 can cooperate to overcome a cell cycle checkpoint induced by mitotic spindle damage. Genes Dev. 10, 2621–2631 (1996).

    Article  CAS  Google Scholar 

  18. Larkins, B. A. et al. Investigating the hows and whys of DNA endoreduplication. J. Exp. Bot. 52, 183–192 (2001).

    Article  CAS  Google Scholar 

  19. Davoli, T., Denchi, E. L. & de Lange, T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 141, 81–93 (2010).

    Article  CAS  Google Scholar 

  20. Kerbel, R. S., Lagarde, A. E., Dennis, J. W. & Donaghue, T. P. Spontaneous fusion in vivo between normal host and tumor cells: possible contribution to tumor progression and metastasis studied with a lectin-resistant mutant tumor. Mol. Cell. Biol. 3, 523–538 (1983).

    Article  CAS  Google Scholar 

  21. Duelli, D. & Lazebnik, Y. Cell fusion: a hidden enemy? Cancer Cell 3, 445–448 (2003).

    Article  CAS  Google Scholar 

  22. Holland, A. J. & Cleveland, D. W. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat. Rev. Mol. Cell. Biol. 10, 478–487 (2009).

    Article  CAS  Google Scholar 

  23. Duelli, D. M., Hearn, S., Myers, M. P. & Lazebnik, Y. A primate virus generates transformed human cells by fusion. J. Cell Biol. 171, 493–503 (2005).

    Article  Google Scholar 

  24. Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007).

    Article  CAS  Google Scholar 

  25. Overholtzer, M. & Brugge, J. S. The cell biology of cell-in-cell structures. Nat. Rev. Mol. Cell Biol. 9, 796–809 (2008).

    Article  CAS  Google Scholar 

  26. Mazzone, M. et al. Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc. Natl Acad. Sci. USA 107, 5012–5017 (2010).

    Article  CAS  Google Scholar 

  27. Guerrero, A. A. et al. Centromere-localized breaks indicate the generation of DNA damage by the mitotic spindle. Proc. Natl Acad. Sci. USA 107, 4159–4164 (2010).

    Article  CAS  Google Scholar 

  28. Wong, C. & Stearns, T. Mammalian cells lack checkpoints for tetraploidy, aberrant centrosome number, and cytokinesis failure. BMC Cell Biol. 6, 6 (2005).

    Article  Google Scholar 

  29. Uetake, Y. & Sluder, G. Cell cycle progression after cleavage failure: mammalian somatic cells do not possess a ‘tetraploidy checkpoint’. J. Cell Biol. 165, 609–615 (2004).

    Article  CAS  Google Scholar 

  30. Talos, F. & Moll, U. M. Role of the p53 family in stabilizing the genome and preventing polyploidization. Adv. Exp. Med. Biol. 676, 73–91 (2010).

    Article  CAS  Google Scholar 

  31. Silkworth, W. T., Nardi, I. K., Scholl, L. M. & Cimini, D. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS ONE 4, e6564 (2009).

    Article  Google Scholar 

  32. Jensen, C. G., Jensen, L. C., Rieder, C. L., Cole, R. W. & Ault, J. G. Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis. Carcinogenesis 17, 2013–2021 (1996).

    Article  CAS  Google Scholar 

  33. Vinciguerra, P., Godinho, S. A., Parmar, K., Pellman, D. & D’Andrea, A. D. Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells. J. Clin. Invest. 120, 3834–3842 (2010).

    Article  CAS  Google Scholar 

  34. Mullins, J. M. & Biesele, J. J. Terminal phase of cytokinesis in D-98s cells. J. Cell Biol. 73, 672–684 (1977).

    Article  CAS  Google Scholar 

  35. Huang, H. et al. Abnormal cytokinesis after X-irradiation in tumor cells that override the G2 DNA damage checkpoint. Cancer Res. 68, 3724–3732 (2008).

    Article  CAS  Google Scholar 

  36. Rappaport, R. Experiments concerning the cleavage stimulus in sand dollar eggs. J. Exp. Zool. 148, 81–89 (1961).

    Article  CAS  Google Scholar 

  37. Abodief, W. T., Dey, P. & Al-Hattab, O. Cell cannibalism in ductal carcinoma of breast. Cytopathology 17, 304–305 (2006).

    Article  CAS  Google Scholar 

  38. Fais, S. Cannibalism: a way to feed on metastatic tumors. Cancer Lett. 258, 155–164 (2007).

    Article  CAS  Google Scholar 

  39. Lugini, L. et al. Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells. Cancer Res. 66, 3629–3638 (2006).

    Article  CAS  Google Scholar 

  40. Cibas, E. S. in Cytology: Diagnostic Principles and Clinical Correlates (eds Cibas, E. S. & Ducatman, B. S.) (Elsevier, 2009).

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Cancer Institute (J.S.B.), NIH GM66492 (R.W.K.) and a grant from the Geoffrey Beene Cancer Research Center at MSKCC (M.O.).

Author information

Authors and Affiliations

  1. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    Matej Krajcovic, Qiang Sun, Evelyn Yao & Michael Overholtzer

  2. BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA

    Matej Krajcovic, Evelyn Yao & Michael Overholtzer

  3. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA

    Nicole B. Johnson & Stuart J. Schnitt

  4. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA

    Guillaume Normand

  5. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    Nicholas Hoover, Andrea L. Richardson & Edmund S. Cibas

  6. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    Randall W. King, Joan S. Brugge & Michael Overholtzer

Authors
  1. Matej Krajcovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicole B. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guillaume Normand
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicholas Hoover
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Evelyn Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrea L. Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Randall W. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Edmund S. Cibas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stuart J. Schnitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Joan S. Brugge
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael Overholtzer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.K., N.B.J., Q.S., G.N., N.H., E.Y. and M.O. designed and carried out experiments, A.L.R. provided human tumours, J.S.B., E.S.C., R.W.K., S.J.S. and M.O. supervised the research, and M.O. and J.S.B. prepared the manuscript.

Corresponding author

Correspondence to Michael Overholtzer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 294 kb)

Supplementary Movie 1

Supplementary Information (MOV 4590 kb)

Supplementary Movie 2

Supplementary Information (MOV 509 kb)

Supplementary Movie 3

Supplementary Information (MOV 6389 kb)

Supplementary Movie 4

Supplementary Information (MOV 8290 kb)

Supplementary Movie 5

Supplementary Information (MOV 1437 kb)

Supplementary Movie 6

Supplementary Information (MOV 1995 kb)

Supplementary Movie 7

Supplementary Information (MOV 2709 kb)

Supplementary Movie 8

Supplementary Information (MOV 1949 kb)

Supplementary Movie 9

Supplementary Information (MOV 2005 kb)

Supplementary Movie 10

Supplementary Information (MOV 1749 kb)

Supplementary Movie 11

Supplementary Information (MOV 1032 kb)

Supplementary Movie 12

Supplementary Information (MOV 111 kb)

Supplementary Movie 13

Supplementary Information (MOV 5139 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krajcovic, M., Johnson, N., Sun, Q. et al. A non-genetic route to aneuploidy in human cancers. Nat Cell Biol 13, 324–330 (2011). https://doi.org/10.1038/ncb2174

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2174

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer