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Mechanisms and mechanics of cell competition in epithelia

Nature Reviews Molecular Cell Biology volume 14, pages 581–591 (2013)Cite this article

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Key Points

  • Cells with reduced protein synthesis capacity are eliminated by apoptosis if they are in contact with normal cells but are viable on their own. Conversely, normal cells are eliminated by the presence of abnormally fast-growing cells. This phenomenon, called cell competition, could have evolved as a mechanism to eliminate slow-growing, dysfunctional or aneuploid cells.

  • Cell competition has now been observed in various mosaic tissues. For example, cells deficient in basolateral determinants are eliminated when surrounded by normal cells but not in their own company. It is not known whether the same cell biological mechanism underlies cell competition caused by polarity mismatch and a growth differential.

  • How cells within a population compare their growth rates and how a steep difference leads to the elimination of loser cells are two questions under intense investigation. So far, alternative splicing of the multipass transmembrane protein Flower is the only molecular marker of loser cells (outcompeted cells).

  • Although it is generally assumed that loser cells are killed by a signal emanating from winner cells (faster-growing cells), it has also been suggested that apoptosis could be an indirect consequence of either engulfment by winner cells or delamination caused by differential growth.

  • Recent work has shown that, in Madin–Darby canine kidney (MDCK) cell culture and in the prospective notum of Drosophila melanogaster, tissue crowding leads to the random expulsion of cells from the epithelium and their subsequent apoptosis.

  • Using an established vertex model of epithelial mechanics, the stresses and strains caused by inhomogeneous growth can be predicted. A group of fast-growing cells could cause planar elongation of the surrounding slower-growing cells. This could be the trigger for subsequent delamination and cell elimination. Therefore, strain caused by mechanical stress could contribute to cell competition.

Abstract

When fast-growing cells are confronted with slow-growing cells in a mosaic tissue, the slow-growing cells are often progressively eliminated by apoptosis through a process known as cell competition. The underlying signalling pathways remain unknown, but recent findings have shown that cell crowding within an epithelium leads to the eviction of cells from the epithelial sheet. This suggests that mechanical forces could contribute to cell elimination during cell competition.

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Figure 1: Topologies of cell competition.
Figure 2: Triggers of cell competition.
Figure 3: Apoptosis in Minute+/− cells occurs in the vicinity of wild-type cells in Drosophila melanogaster imaginal discs.
Figure 4: Direct and indirect triggers of apoptosis.
Figure 5: Predicted stresses and strains in an around a fast-growing clone of cells.

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Acknowledgements

The authors thank K. Rizzoti and R. Lovell-Badge for discussions about mouse mosaics. J.-P.V. is supported by the Medical Research Council (MRC) and the European Research Council (ERC) (WNTEXPORT),L.A.B.-L. by the Wellcome Trust (082694/z/07/z) and A.G.F. by the Engineering and Physical Sciences Research Council (EPSRC) (EP/I017909/1) and Microsoft Research Cambridge.

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Authors and Affiliations

  1. Medical Research Council (MRC) National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK

    Jean-Paul Vincent & L. ALberto Baena-Lopez

  2. Centre for Mathematical Biology, Mathematical Institute, 24–29 St Giles', Oxford, OX1 3LB, UK

    Alexander G. Fletcher

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Correspondence to Jean-Paul Vincent.

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FURTHER INFORMATION

CancerStats

FlyBase

PowerPoint slides

Glossary

Genetic mosaics

Tissues comprised of genetically distinct cells. In Drosophila melanogaster, these are typically generated by inducing mitotic recombination in a heterozygous background, thus creating twin clones, one being homozygous wild type and the other homozygous mutant at a given locus.

Blastocysts

Early mammalian embryos composed of about 100 cells. Embryonic stem cells are injected into blastocysts to generate chimaeras before implantation into a surrogate mother.

Chimaeras

Embryos comprising cells of two distinct genotypes. They are usually generated by cell transplantation.

Apoptosis

One of the main processes leading to cell death. It involves the activation of a proteolytic cascade comprising initiator and executioner caspases.

Aneuploid cells

Cells that have lost or gained entire chromosomes or large chromosomal fragments as a consequence of chromosome rearrangements.

Myc

A proto-oncoprotein that controls ribosome biosynthesis, translational activity and other essential cellular activities.

Contact inhibition

A phenomenon whereby cells stop growing as their density increases.

Imaginal discs

Epithelial pouches that grow inside insect larvae and give rise to most adult structures during metamorphosis. They are extensively used to study pattern formation and growth control.

Apical–basal determinants

Proteins that ensure apical–basal polarity. Apical determinants such as atypical protein kinase A and basolateral determinants such as Scribble or Lethal giant larvae typically oppose each other's activity thus ensuring the partitioning of distinct domains.

Madin–Darby canine kidney cells

(MDCK cells). The best-characterized epithelial cell line.

Neoplastic overgrowth

Overgrowth that is accompanied by loss of polarity and general disorganisation of the tissue.

Hyperplastic overgrowth

Overgrowth that maintains cell polarity and tissue integrity. It is often accompanied by tissue folds.

Caspase

A class of proteases that initiate or execute apoptosis.

JUN N-terminal kinase

(JNK). The key mediator of a kinase cascade that is often activated by stress. Depending on the context, it can trigger cell migration or apoptosis.

hid

A gene encoding one of the five pro-apoptotic proteins in Drosophila melanogaster. It inhibits the activity of DIAP1 (D. melanogaster inhibitor of apoptosis 1), which itself inhibits caspases.

Epithelial-to-mesenchymal transition

(EMT). A process whereby epithelial cells lose their epithelial characteristics (for example, polarity), detach from the epithelium and become migratory.

PTEN

A negative regulator of insulin signalling. Loss of PTEN is associated with numerous cancers.

Tuberous sclerosis complex 1

(TSC1). A tumour suppressor that negatively regulates insulin signalling.

PI3K

A key mediator of insulin signalling. Upon activation of the insulin receptor, it converts phosphatidylinositol-4,5-bisphosphate to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3), an activity that is antagonized by PTEN. PtdIns(3,4,5)P3 activates AKT, which in turn triggers further downstream events.

Adherens junctions

Molecular complex that mediates cell–cell adhesion in epithelia. They are typically organized in belts that surround every cell near the apical side.

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Vincent, JP., Fletcher, A. & Baena-Lopez, L. Mechanisms and mechanics of cell competition in epithelia. Nat Rev Mol Cell Biol 14, 581–591 (2013). https://doi.org/10.1038/nrm3639

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