Skip to main content
Log in

Stages of cell cannibalism–entosis–in normal human keratinocyte culture

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript


Entosis is a type of cell cannibalism during which one cell penetrates into another cell and usually dies inside it. Researchers mainly pay attention to initial and final stages of entosis. Besides, tumor cells in suspension are the primary object of studies. In the present study, we investigated morphological changes of both cells-participants of entosis during this process. The substrate-dependent culture of human normal keratinocytes HaCaT was chosen for the work. A combination of light microscopy and scanning electron microscopy was used to prove that one cell was completely surrounded by the plasma membrane of another cell. We investigated such “cell-in-cell” structures and described the structural and functional changes of both cells during entosis. The outer cell nucleus localization and shape were changed. Gradual degradation of the inner cell nucleus and of the junctions between the inner and the outer cells was revealed. Moreover, repeated redistribution of the outer cell membrane organelles (Golgi apparatus, lysosomes, mitochondria, and autophagosomes), rearrangement of its cytoskeleton, and change in the lysosomal, autophagosomal, and mitochondrial state in both entotic cells were observed during entosis. On the basis of these data, we divided entosis into five stages that make it possible to systematize description of this type of cell death.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others



programmed cell death


scanning electron microscopy


  1. Kerr, J. F. R., Wyllie, A. H., and Curruie, A. R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics, Br. J. Cancer, 26, 239257.

    Article  Google Scholar 

  2. Galluzzi, L., Bravo-San Pedro, J. M., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria, R., Debatin, K. M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., Lopez-Otin, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. C., Martin, S. J., Martinou, J. C., Medema, J. P., Meier, P., Melino, S., Mizushima, N., Moll, U., Munoz-Pinedo, C., Nunez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Pinton, P., Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., and Kroemer, G. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015, Cell Death Differ., 22, 58–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E. S., Baehrecke, E. H., Blagosklonny, M. V., ElDeiry, W. S., Golstein, P., Green, D. R., Hengartner, M., Knight, R. A., Kumar, S., Lipton, S. A., Malorni, W., Nunez, G., Peter, M. E., Tschopp, J., Yuan, J., Piacentini, M., Zhivotovsky, B., and Melino, G. (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death, Cell Death Differ., 12 (Suppl. 2), 1463–1467.

    Article  Google Scholar 

  4. Yuan, J., and Kroemer, G. (2010) Alternative cell death mechanisms in development and beyond, Genes Dev., 24, 2592–2602.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Overholtzer, M., Mailleux, A. A., Mouneimne, G., Normand, G., Schnitt, S. J., King, R. W., Cibas, E. S., and Brugge, J. S. (2007) A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion, Cell, 131, 966979.

    Article  Google Scholar 

  6. Doukoumetzidis, K., and Hengartner, M. O. (2008) Dying to hold you, Nature, 451, 530–531.

    Article  CAS  PubMed  Google Scholar 

  7. Guadamillas, M. C., Cerezo, A., and Del Pozo, M. A. (2011) Overcoming anoikis–pathways to anchorage-independent growth in cancer, J. Cell. Sci., 124, 3189–3197.

    Article  CAS  PubMed  Google Scholar 

  8. Ishikawa, F., Ushida, K., Mori, K., and Shibanuma, M. (2015) Loss of anchorage primarily induces non-apoptotic cell death in a human mammary epithelial cell line under atypical focal adhesion kinase signaling, Cell Death Dis., 6, 1–12.

    Article  Google Scholar 

  9. Krajcovic, M., Johnson, N. B., Sun, Q., Normand, G., Hoover, N., Yao, E., Richardson, A. L., King, R. W., Cibas, E. S., Schnitt, S. J., Brugge, J. S., and Overholtzer, M. (2011) A non-genetic route to aneuploidy in human cancers, Nat. Cell Biol., 13, 324–330.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Mazzone, M., Selfors, L. M., Albeck, J., Overholtzer, M., Sale, S., Carroll, D. L., Pandya, D., Lu, Y., Mills, G. B., Aster, J. C., Artavanis-Tsakonas, S., and Brugge, J. S. (2010) Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells, Proc. Natl. Acad. Sci. USA, 107, 5012–5017.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Wan, Q., Liu, J., Zheng, Z., Zhu, H., Chu, X., Dong, Z., Huang, S., and Du, Q. (2012) Regulation of myosin activation during cell–cell contact formation by Par3-Lgl antagonism: entosis without matrix detachment, Mol. Biol. Cell, 23, 2076–2091.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Overholtzer, M., and Brugge, J. S. (2008) The cell biology of cell-in-cell structures, Nat. Rev. Mol. Cell Biol., 9, 796809.

    Article  Google Scholar 

  13. Sun, Q., Cibas, E. S., Huang, H., Hodgson, L., and Overholtzer, M. (2014) Induction of entosis by epithelial cadherin expression, Cell Res., 24, 1288–1298.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Gama, A., and Schmitt, F. (2012) Cadherin cell adhesion system in canine mammary cancer, Vet. Med. Int., 2012, 1–8.

    Article  Google Scholar 

  15. Hirokawa, N. (1996) Organelle transport along microtubules–the role of KIFs, Trends Cell Biol., 6, 135–141.

    Article  CAS  PubMed  Google Scholar 

  16. Welte, M. A. (2004) Bidirectional transport along microtubules, Curr. Biol., 14, 525–537.

    Article  Google Scholar 

  17. Balzer, E. M., and Konstantopoulos, K. (2012) Intercellular adhesion: mechanisms for growth and metastasis of epithelial cancers, Wiley Interdiscip. Rev. Syst. Biol. Med., 4, 171–181.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Florey, O., Gammoh, N., Kim, S. E., Jiang, X., and Overholtzer, M. (2014) V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation, Autophagy, 11, 8899.

    Google Scholar 

  19. Florey, O., Kim, S. E., Sandoval, C. P., Haynes, C. M., and Overholtzer, M. (2011) Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes, Nat. Cell Biol., 13, 1335–1343.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Green, S. A., Zimmer, K. P., Griffiths, G., and Mellman, I. (1987) Kinetics of intracellular transport and sorting of lysosomal membrane and plasma membrane proteins, J. Cell Biol., 105, 1227–1240.

    Article  CAS  PubMed  Google Scholar 

  21. Rohrer, J., and Kornfeld, R. (2001) Lysosomal hydrolase mannose 6-phosphate uncovering enzyme resides in the trans-Golgi network, Mol. Biol. Cell, 12, 1623–1631.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Fukuda, M. (1991) Lysosomal membrane glycoproteins. Structure, biosynthesis, and intracellular rafficking, J. Biol. Chem., 266, 21327–21330.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to A. S. Garanina.

Additional information

Original Russian Text © A. S. Garanina, L. A. Khashba, G. E. Onishchenko, 2015, published in Biokhimiya, 2015, Vol. 80, No. 11, pp. 1688-1697.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM15-215, September 13, 2015.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garanina, A.S., Khashba, L.A. & Onishchenko, G.E. Stages of cell cannibalism–entosis–in normal human keratinocyte culture. Biochemistry Moscow 80, 1469–1477 (2015).

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: