www.elsevier.com/locate/yexcr

Experimental Cell Researc

Review

The competitive nature of cells

Begona Dıaz, Eduardo Moreno*

Centro Nacional de Investigaciones Oncologicas (C.N.I.O), Melchor Fernandez Almagro, 3. E-28029 Madrid, Spain

Received 2 February 2005, revised version received 2 February 2005

Available online 18 April 2005

Abstract

The possibility that cells of multicellular organisms may compete with one another has been postulated several times. It was

experimentally confirmed in Drosophila, probably for the first time, when cells with different metabolic rates were mixed: cells that would

have been viable on their own disappeared due to the presence of metabolically more active cells. After almost 30 years of neglect, genetic

analysis in Drosophila has started to reveal a gene network that regulates the competitive behavior of cells. If the genes regulating cellular

competitiveness in Drosophila have a conserved function in mammals, the study of cell competition could have an impact in several

biomedical fields, including functional degeneration, cancer, or stem cell therapies.

D 2005 Elsevier Inc. All rights reserved.

Keywords: Drosophila; Cell competition; Stem cell

Contents

A genetic network for cell competitiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

Revealing cellular fitness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Stem cells and cell competition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

A genetic network for cell competitiveness

The possibility that cells of multicellular organisms may

compete with one another has been postulated several times

over the past two centuries. In 1888, Wilhelm Roux

proposed the idea of a cellular struggle for survival during

development [1]. Wilhelm Roux transferred Charles Dar-

win’s theory of the struggle for existence to the fight among

cells and ‘‘parts’’ of the organism in the process of

ontogenesis. As evidence for the conflict between cell

types, he referred to pathological processes in which cells of

one tissue start to invade another [1]. However, his idea

faced a lot of opposition, since the harmonic behavior of

0014-4827/$ - see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.yexcr.2005.03.017

* Corresponding author. Fax: +34 912 246 980.

E-mail address: emoreno@cnio.es (E. Moreno).

cells within multicellular organisms argued against a fierce

competition among their parts and in favor of a cooperation

of the different cell types. Twenty years later, Ilya

Mechnikov considered the likelihood of cells continuously

fighting to survive in light of his studies on phagocytosis,

but did not developed the idea much further. During his

studies on the structure of the nervous system, Santiago

Ramon y Cajal was even more explicit, suggesting that

during neurogenesis there might be a competitive struggle

among neurons for space and nutrition. With the discovery

of growth factors, the idea of neuronal competition at the

level of axon pathfinding was recovered as a marginal part

of the neurotrophic theory by Rita Levy-Montalcini and

refined by Dale Purves and Martin Raff [2,3]. In this view,

all cells require signals from their neighbors to survive [3].

This social nature of cells is now widely accepted: the

h 306 (2005) 317 – 322

B. Dıaz, E. Moreno / Experimental Cell Research 306 (2005) 317–322318

dependence of most cell types on survival signals provided

by their neighbors also faces no opposition by those that

view the cellular societies of multicellular organisms as a

gathering of genetically programmed ‘‘harmonic coopera-

tors’’. Cells need each other to survive, so that must provide

a solid ground for cooperation [3]. But what happens if the

resources required for cell survival are limiting? Then some

cells must die. Do they die randomly, without noticing, in a

passive non-competitive way, or do they actively compete

among them for the limiting resources and struggle to

survive?

This simple concept of cells competing among them

remained difficult to prove, and hence remained controver-

sial. The main reason why it was difficult to prove

experimentally is because it is not easy to distinguish between

a competitive interaction that results in the death of one of the

competitors and a passive non-competitive death, or even a

‘‘self-sacrifice’’. Examples of such ‘‘self-sacrifice’’ do

actually exist in multicellular animals. One famous example

is the death of cells in the nematode Caenorhabditis elegans,

where cells kill themselves for the good development of the

organism, accepting their fatal fate without trying to fight

back or compete actively with the neighbors [4]. But do

competitive interactions among cells also exist? For a

competitive interaction between cells to be demonstrated

unequivocally, an experimental situation must be created

where the interaction between two defined groups of cells can

be monitored, so that the effects on one population can be

proved to be due to the presence of the other cell group. As

opposed to a random mechanism, a truly competitive

situation will then cause a decrease of cell numbers in the

weaker of the two populations and a corresponding increase

in the other. Given enough time, the group with the

competitive advantage will take over, and eventually

eliminate, the weaker population.

Cellular competition was experimentally confirmed in

Drosophila, probably for the first time, almost a century

after Roux’s initial formulation, when cells with different

metabolic rates were mixed: cells that would have been

viable on their own disappeared due to the presence of

metabolically more active cells [5]. The particular mutants

used are the so-called Minutes, which are mutants in

ribosomal proteins. The first Minute genes were discovered

by Thomas Hunt Morgan and Calvin Bridges at Columbia

University in New York and later at Caltech in Pasadena.

Nowadays, there are at least 50 different Minute genes,

since many mutations in several ribosomal proteins have

been obtained over the years. Minute homozygote flies are

cell lethal, due to a lack of functional ribosomes and no

protein synthesis, but Minute heterozygote flies are perfectly

viable and normally sized, although it takes them a few days

longer than wild-type flies to complete embryonic develop-

ment, probably due to the lack of a fully active ribosomal

machinery. The crucial observation regarding competitive

interactions came when mosaics containing both population

types, Minute heterozygous cells together with wild-type

cells, were created [5]. The experiment was performed by

two graduate students, Gines Morata and Pedro Ripoll at the

laboratory of Antonio Garcıa-Bellido in the CSIC in

Madrid. Before the experiment was performed, Antonio

Garcıa-Bellido predicted that the growth delay will not be

cell autonomous and that the cells will not proliferate at

different rates when mixed. That was not the case, and cells

did indeed proliferate at different rates. This caused Garcıa-

Bellido not to co-author that paper. But even more

strikingly, Minute heterozygous cells not only proliferated

more slowly. Unlike what was expected, the Minute

heterozygote cells were not even viable in the Drosophila

wing anymore. Presumably, the presence of wild-type

surrounding cells must be killing them, despite they would

have been viable on their own, a possibility that was

confirmed later [6]. Morata and Ripoll submitted the paper

to several journals and was rejected. The reviewers did not

believe it. The idea of cells competing among them during

development was ‘‘havoc’’ and ‘‘nonsense’’ and the referees

felt there should be something wrong with the experiment,

since cells need to cooperate rather than compete. The paper

was finally published in Developmental Biology in 1975,

and since then, it has become a highly cited paper.

OK, now we believe it, so what? It appears clear that

cells can fight in many epithelial tissues during fly

development if they have different metabolic rates, but

should we care? And if we do, can we find genes regulating

cell competitiveness?

In principle, competition among cells provides an

efficient mechanism for selecting cell quality and thereby

ensuring that the requisite cellular tasks will be done by the

most efficient ones. It seems unlikely that such an effective

mechanism to select for cell fitness is confined to flies. Most

importantly, after almost 30 years of neglect [5,6], genetic

analysis in Drosophila has started to reveal a gene network

that controls cell competition [6]. Just as there are pathways

that regulate the cell cycle [7–9] or programmed cell death

[10], at least in the fly there seems to be genes that regulate

cell competitiveness [6,11–14]. In support of a global

relevance, we will speculate that genetically programmed

cell competition is used throughout the animal kingdom

during development and homeostasis. To unify the follow-

ing examples, in addition to the classical term of cell

competition, and without the aim of substituting it, but

rather to more rigorously define a group of common

phenomena, we propose the term cytagon (from the ancient

Greek ‘‘cell war’’), as synonym of ‘‘programmed cell

competition’’.

Classical experiments in Drosophila pioneered the idea

that cells compete with each other to fill a limited space that

appears to be mapped out in advance [5,11]. But what can

the success of cells in the battlefield be attributed to? And

how are the dimensions of such a field determined? The

simplest possibility would provide answers to both ques-

tions by a single molecular principle, i.e., that the same

factor(s) that selects for cell quality are also governing field

B. Dıaz, E. Moreno / Experimental Cell Research 306 (2005) 317–322 319

size. This appears to be the case in Drosophila, where the

main factor controlling cell competition [6], Decapentaple-

gic (Dpp, a homologue of bone morphogenetic proteins

(BMPs)), is also responsible for the spatial dimensions of

the field within which cells compete [15,16]. Is this just a

coincidence, or could it be advantageous to regulate quality

and size via the same molecule? Could this even be a

general principle?

It is possible to spot other cases in development and

homeostasis where cell competition may occur within a

limited space predefined by a mighty morphogen. As a

starting example, the random patterns of proliferation and

apoptosis that are normally observed during embryogenesis

in mammals may be the outputs of a continuous deve-

lopmental cytagon. Recent preliminary evidence suggests

that cell competition may be at play in mammals during

embryonic development [17], in a similar way as it had been

described in Drosophila. If the process is finally confirmed

to be present during development [17], it is likely that a

similar situation may occur later, during homeostasis of self-

renewing cell pools like stem cells [18] or lymphocytes [19].

In the hematopoietic system, new cells are constantly

produced but the size of the stem cell niche remains

constant. There is a continuous migration of cells leaving

from and returning to the niche. It is possible that for blood

cells to re-engraft in the bone marrow niche, cytagon may be

at play, as a mechanism to ensure that the size of the pool is

maintained and the most competitive cells are selected to

remain. BMPs have been implicated in regulating survival

and maintenance of the bone marrow stem cell population

[20] and thus may define its size and quality. Also,

controlling size and quality of the lymphocyte pool is of

crucial importance in mammals: the number of lymphocytes

must be large enough to detect a diverse range of pathogens,

but there is limited physical space in the body to host all

lymphocytes [19]. Due to this size constraint, the immune

system has to sacrifice some of the pre-existing cells to

make room for new lymphocytes that are continuously

produced. In several of these cases, cell competition could

be epigenetically regulated to favor the expansion of one

cell population within a limited space at the expense of

another population or cell type.

Fig. 1. Programmed cell competition or cytagon could act as a cell selection

mechanism at the population level. (A) Cell selection inside a population

based upon growth factor accessibility. Growth factor (red spots) is

available in limiting quantities, and only those cells in which growth factor

signaling is above a threshold can survive. In this scenario, the mechanism

sets the ‘‘sub-optimal’’ threshold for survival. (B) Growth factor (red spots)

is not limiting, so all the cells in the population have enough growth factor-

dependent survival signaling. However, not all of them are equally

competitive. Cytagon allows the most competitive to eliminate the others

after ‘‘cell– cell-comparison’’. By this mechanism, cells that could survive

by their own are eliminated by the presence of more fit cells. In this

scenario, this mechanism would set the ‘‘optimal’’ threshold for survival.

Revealing cellular fitness

The surest foundation is quality.

Andrew Carnegie.

To achieve epigenetic modulation, cell competition must

be enabled genetically. But by what means is cell

competitiveness assessed and compared from cell to cell?

Some of the genes involved in this process are starting to be

identified, and it appears that endocytic internalization of

extracellular ligands could be one of the principles by

which cell competition is implemented on a population

basis [6].

While endocytosis has traditionally been considered a

slow desensitization mechanism for signal transduction

pathways triggered by extracellular ligands, more and more

evidence indicates that endocytosis plays an important

positive role in the activation and propagation of certain

signaling pathways [21], including Dpp signaling [6,22,23].

Two theoretical frameworks, depending on whether a ligand

is provided in limiting supply or in excess, can account for

cell selection based on ligand internalization. If the

extracellular ligand concentration is limiting, a ‘‘winner-

takes-it-all’’ situation could apply (Fig. 1). Weak cells which

are metabolically less active do not obtain enough survival

factor and die. Several mechanisms can limit ligand

concentration in the intercellular space, such as the rate of

synthesis in producing cells, sequestration of free ligand in

the extracellular matrix, changes in cell number, and the fate

of the ligand in the endocytic pathway (degradation versus

recycling). From the perspective of cell competition, the

endocytic pathway is of special interest as it could

mechanistically couple the availability of free ligand with

competition for ligand internalization [6]. A shift of the

balance towards ligand degradation decreases the amounts

of available growth factors and thereby reduces organ size

[22]. Tipping the balance towards recycling [24] would

lower cytagon and, simultaneously, increase organ size. The

connection between organ size and cell competition would

only correlate because the same factor is used for inducing

growth and for revealing cell fitness [6,16].

B. Dıaz, E. Moreno / Experimental Cell Research 306 (2005) 317–322320

But what if the ligand is not limiting, as it may be the case

for a morphogen? Then a cell–cell communication mecha-

nism could permit cells to compare their respective signaling

levels [25,26] and cause a ‘‘you lose’’ signal to be sent to the

less efficient cell(s), which as a result would undergo

apoptosis (Fig. 1). It is possible that members of the TNF

superfamily might represent a molecular implementation of

such a ‘‘you lose’’ signal [27], but the discovery of the genes

implicated in the cell–cell communication mechanism that

may help cells compare relative signaling levels among them

remains a challenge. Such hypothetical mechanism may help

one cell to spy the signaling levels of the neighboring cells in

a first step, and trigger apoptosis through a second step using

the ‘‘you lose signal’’. Is the existence of such ‘‘cell–cell

spying system’’ wild speculation? We do not think so.

Several lines of evidence coming from studies of the

Drosophila imaginal discs suggest that such a spying genetic

network must exist in order to allow cells to monitor the

signaling levels of their neighbors [6,25,26], but the

molecular nature of such spy molecules remains unknown.

We would like to note that such a ‘‘you lose’’ scenario has the

advantage that it does not depend on conditions of limiting

survival factor(s), since cells with different signaling levels,

due for example to different rates of endocytosis, will be able

to still spy and recognize each other, even if the extra-cellular

concentrations of ligand are not limiting.

Until here, cell competition makes perfect sense as a

physiological mechanism to select cells of optimal quality

and to maximize tissue fitness [6]. However, a surprising

discovery has been made with the identification of genes that

are able to induce cell competition above wild-type levels,

what has been termed super-competition [13,14]. In partic-

ular, it has been recently proposed that oncogenes of the myc

family can transform cells into super-competitors [13,14],

able to expand at the expense of normal surrounding tissue by

killing it by apoptosis, in a way that total cell numbers are

unchanged [14]. This phenomenon has been hypothesized to

be involved in early stages of cancer formation (Fig. 2) and in

the explanation of poorly understood clinical observations

like the one termed ‘‘field cancerization’’ [14]. A gene

duplication event, a translocation, or some other means of

causing heritable overexpression of a human myc family

member may help an originally transformed cell to success-

Fig. 2. Super-competition could contribute to early cancer progression. A mutati

‘‘super-competitor’’ (A), able to undergo clonal expansion at the expense of the n

Secondary mutations in a super-competitor background could initiate tumor form

fully establish its descendants within an epithelial cell group.

If such super-competitor cells behave like those in Droso-

phila, their expansion would occur at the expense of

surrounding cells and hence not be detectable by morpho-

logical examination [14]. Competition for growth and

survival factors could help expand the initial pre-cancerous

population within a local trophic compartment. Further

oncogenic mutations are then more likely to occur in an

expanded population of cells that already exhibit this

competitive advantage (Fig. 2). The discovery comes as a

surprise, because there is no clear physiological function for

it. Could cell super-competition be modulated epigenetically,

for example, to contribute to tissue repair and regeneration,

by promoting the proliferation of new cells at the expense of

the old damaged, and/or displaced, tissue? In any case, from a

historical point of view, super-competition can be seen as a

possible validation of Roux controversial idea of a cellular

struggle for survival and its connection to pathological

processes, during which cells of one region start to invade

the territory occupied by another population [1]. Study of

model organisms such as yeast, C. elegans, sea urchins, or

Drosophila has pioneered crucial contributions to processes

with important implications in neoplasia like the nature and

role of environmental mutagens [28], cell proliferation [7–9],

or apoptosis [4,10]. May the phenomenon of super-competi-

tion described in Drosophila [13,14] also apply to humans

and help us understand tumor progression [29,30]? In this

regard, the competitive expansion of super-competitor cells

in Drosophila reveals a scenario that is strikingly

reminiscent of, and may explain, the clinical finding

termed ‘‘field cancerization’’, in which a field of cells of

monoclonal origin is associated with a proliferative

advantage and expands at the expense of normal tissue.

Initially, neither invasive growth nor aberrant histology are

present; but as the field becomes larger, additional genetic

hits give rise to various subclones that eventually evolve

into primary and ‘‘second field tumors’’ that share a

common clonal origin [14,29,30].

Dmyc, like other myc family proteins, is a transcription

factor known to regulate genes involved in cellular

metabolism, like ribosomal proteins. One of the hypothesis

as to the way by which increased dMyc levels confer a

proliferation advantage is that cells with an enhanced

on of a myc proto-oncogen could transform a normal epithelial cell into a

ormal surrounding tissue without any morphological alterations (B and C).

ation (D).

B. Dıaz, E. Moreno / Experimental Cell Research 306 (2005) 317–322 321

translational capacity might compete more successfully than

surrounding cells for the active uptake of extracellular

survival and growth factors, and in doing so may expand

within the community by killing or attenuating normal cells

[14]. Likewise, tumors with high metastatic potential may be

explained by success in cell competition during tissue

invasion. The ability of advanced tumors to metastasize

may thus be linked to the same early event conferring a

Darwinian advantage to primary tumors. Due to the

increasing evidence favoring a role for stem cells in tumor

formation [31,32], it would be interesting to know if cell

competition induced by oncogenes like myc can occur in

stem cell niches [44]. Moreover, in adult tissues that undergo

continuous cell turnover, stem cells are responsible for tissue

renewal throughout adult life. Therefore, maintenance of

sufficient number of optimal quality stem cells may be

essential to ensure efficient tissue renewal and repair. But, is

there a quality control that helps selecting optimal stem cells

at a population level?

Stem cells and cell competition

Should I stay or should I go now?

If I go there will be trouble. . .And if I stay it will be double!

‘‘Combat Rock’’. The Clash, 1982.

Adult stem cells are often found at specific locations

called niches that provide the special tissue microenviron-

ment required for the stem cell to maintain a stable

undifferentiated state [33–35]. Very much like a young girl

in the dilemma to leave the family house, the daughters of

proliferating stem cells must face the fate decision whether

to remain in the niche, youthful and undifferentiated,

preserving the pool of stem cells; or to leave the special

microenvironment and differentiate into novel cell types

[33–35]. The mechanisms by which stem cells decide to

remain in the niche or to leave it are a major player in

regulating the balance between stem cell self-renewal and

differentiation. If all of them go, ‘‘there will be trouble’’,

since the niche will be emptied and the tissue will

degenerate sooner or later, but if they all stay, the number

of stem cells ‘‘will be double’’. How is this dilemma

resolved? Should I stay or should I go?

Two main hypothesis have been proposed to explain the

mechanisms governing stem cell self-renewal [33–36].

The first suggests that the process cells use to remain or

exit the stem cell niche is deterministic and based in

asymmetric cell divisions. Asymmetric cell divisions could

be implemented by orienting the plane of cell division so

that one of the daughter cells remains in the niche while the

other moves away as division proceeds. The second

postulates a probabilistic mechanism, where cells do not

divide in any oriented direction, but since the niche is a

fixed space, some cells may end out of the niche. Although

the original concept of niche favored the probabilistic

mechanism [36], recent evidence is accumulating that

asymmetric cell divisions may be a more common [37–

39], if not universal, mechanism to regulate the balance

between differentiation and self-renewal.

The first cellular network to be defined at the functional

level as a niche was identified in the Drosophila ovary by

Ting Xie and Allan Spradling [40]. Although the niche was

described as a functional unit in the year 2000, the number

of stem cells that should reside in that niche had been

previously estimated, before even seeing them, in a

beautiful genetic study done by Eric Wieschaus and Janosz

Szabad in 1979 [41]. The number of germline stem cells of

the ovary was then estimated to be around 2.8 per niche,

inferred by the proportions of eggs produced by mosaic flies

[41]. Since cells are indivisible units, this decimal number

predicted that most niches will contain either two or three

stem cells each, assuming there is not much variation from

one ovary germ stem cell niche to another. Each one of these

2 or 3 stem cells is attached tightly to the niche [42] and is

maintained undifferentiated by the extracellular stem cell

factor Decapentaplegic (Dpp), a BMP2/4 homologue [43].

A niche geometer might characterize the niche as a box of

somatic cells harboring the germline stem cells. Dpp is

thought to be produced by those somatic cells surrounding

the stem cells and secreted to the territory occupied by the 2

or 3 stem cells that need it to divide and self-renew [43].

The germ stem cell divides continuously, approximately

once per day, and after each division, one daughter cell stays

in the niche as a stem cell, while the other moves out of the

niche and begins a program of differentiation that ultimately

will produce one oocyte and 15 nurse cells.

It has been recently shown [44] that cell competition can

contribute to select stem cells of optimal quality within the

Drosophila ovary germ line niche, in a similar way as it

does in the Drosophila wing [6]. Results are consistent with

a model where dpp controls niche size [40,43] and d-Myc

activates the competitive behavior of cells, so that cells

within the niche are induced to compete for Dpp [44]. d-

Myc expression in the niche seems to create a cell-based

competitive environment oriented to maximize cellular

fitness among stem cells [44]. The existence of a mechanism

governing stem cell renewal oriented to select for cell

quality and maximize the cellular fitness of the cells that

remain within the niche has the caveat that the accumulation

of mutations transforming cells into super-competitors may

promote the generation of cancer stem cells. Is it possible

that animals have developed mechanisms to promote cell

competition while reducing super-competition in order to

maintain the cell fitness selection mechanisms while

reducing the occurrence of tumor promoting processes?

Finally, one could ask whether cytagon could serve as a

target for therapeutic interventions to combat processes such

as functional degeneration and aging [6] or cancer [13,14],

or to improve (or supplant) stem cell therapies [44], i.e.,

medicine in search of excellence. In any case, those are all

challenges for the future study of this field of research. After

B. Dıaz, E. Moreno / Experimental Cell Research 306 (2005) 317–322322

all, cells are an organism’s most important asset and quality

may be its surest foundation.

Acknowledgments

We thank O. Fernandez-Capetillo and C. Rhiner for

reading the manuscript and suggestions. Work is supported

by a Caja Madrid-CNIO junior group leader grant to EM.

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