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Stemming Tumoral Growth: A Matter of Grotesque Organogenesis
Marisa M. Merino 1, *,†
and Jose A. Garcia-Sanz 2, *,†
1
2
*
†
Department of Biochemistry, Faculty of Sciences, University of Geneva, 1205 Geneva, Switzerland
Department of Molecular Biomedicine, Centro de Investigaciones Biologicas Margarita Salas,
Spanish National Research Council (CIB-CSIC), 28040 Madrid, Spain
Correspondence: [email protected] (M.M.M.); [email protected] (J.A.G.-S.)
Both authors contributed equally to this work and should be considered Senior co-authors.
Abstract: The earliest metazoans probably evolved from single-celled organisms which found the
colonial system to be a beneficial organization. Over the course of their evolution, these primary
colonial organisms increased in size, and division of labour among the cells became a remarkable
feature, leading to a higher level of organization: the biological organs. Primitive metazoans were the
first organisms in evolution to show organ-type structures, which set the grounds for complex organs
to evolve. Throughout evolution, and concomitant with organogenesis, is the appearance of tissuespecific stem cells. Tissue-specific stem cells gave rise to multicellular living systems with distinct
organs which perform specific physiological functions. This setting is a constructive role of evolution;
however, rebel cells can take over the molecular mechanisms for other purposes: nowadays we know
that cancer stem cells, which generate aberrant organ-like structures, are at the top of a hierarchy.
Furthermore, cancer stem cells are the root of metastasis, therapy resistance, and relapse. At present,
most therapeutic drugs are unable to target cancer stem cells and therefore, treatment becomes a
challenging issue. We expect that future research will uncover the mechanistic “forces” driving organ
growth, paving the way to the implementation of new strategies to impair human tumorigenesis.
Keywords: organogenesis; tumorigenesis; stem cells; cancer stem cells; cell competition; scaling;
size; growth
Citation: Merino, M.M.; Garcia-Sanz,
J.A. Stemming Tumoral Growth: A
Matter of Grotesque Organogenesis.
Cells 2023, 12, 872. https://doi.org/
10.3390/cells12060872
Academic Editor: Fabrizio Marcucci
Received: 17 February 2023
Revised: 7 March 2023
Accepted: 9 March 2023
Published: 11 March 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
1. Early Metazoans and Division of Labour
The emergence of metazoan life can be traced back to 700–800 million years ago [1].
Primitive metazoans probably evolved from single-celled organisms which found the
colonial system to be a beneficial organization [2–6]. Over the course of evolution, these
primary colonial organisms increased in size, and division of labour among the cells became
a remarkable feature [7]. Cells within the colony specialized for different functions in order
to obtain the required resources, perhaps while reducing conflicts among the members of
the colony [8]. This evolutionary process led to a higher level of biological organization,
which in current complex organisms has developed into anatomical units, with specialized
cells that form the biological organs, which perform specific functions [2–6].
Porifera (commonly referred to as sponges) are thought to be the most ancient, extant
metazoans on earth, and therefore provide insights into the earliest processes in metazoan
evolution [2,9]. These living fossils already carry some signalling pathways, including Wnt,
TGF-Beta, and Hedgehog [10], which are conserved across metazoan life. The sponge’s
anatomy is formed by two distinct epithelial cell layers, with a few cell types showing different degrees of motility [11]. Indeed, sponges were the first organisms in evolution to show
organ-type structures. Sponge epithelia are polarised, sealing and controlling the passage
of solutes and therefore their internal milieu. This proto-skin might be evolutionary the
origin of the first biological organ in the known life, allowing biochemical communication
among cells and probably setting the grounds for complex organs to evolve [12].
4.0/).
Cells 2023, 12, 872. https://doi.org/10.3390/cells12060872
https://www.mdpi.com/journal/cells
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2. The Emergence of Tissue-Specific Stem Cells
Throughout evolution, and concomitant with organogenesis, is the appearance of
tissue-specific stem cells in the animal and plant kingdoms [13]. Stem cells sustain cell
renewal, replace and regenerate damaged tissues, maintaining organ function and homeostasis [14–16]. Historically, the term “stem cell” was coined by the German physician
and zoologist Ernest Haeckel (1834–1919). While recording his findings, he extraordinarily
blended science and art by hand-drawing the organisms he observed, from mountaintops
to oceans [17]. Curiously, Haeckel introduced the term with an evolutionary connotation.
As a supporter of Darwin’s theory of evolution, he described phylogenetic trees, which he
called “stem trees”, as representing the evolution of organisms from common ancestors. In
this context, he used the term “stem cell” to refer to the unicellular ancestor of all multicellular organisms, as well as the fertilized egg, which gives rise to all cell types in living
organisms [18].
Despite this early usage of the term, it was not until the 1960s that the Canadian scientists Ernest A. McCulloch and James E. Till characterized what we now refer as a stem cells,
and developed an assay to analyse the potential of early blood-forming progenitor cells
from bone marrow to self-renew and differentiate into several blood cell types (Figure 1).
These pioneering studies described the hallmark properties of stem cells, characterized by
the ability to self-renew and differentiate in a hierarchical organization [19–21]. Going back
to the primitive metazoan organisms, sponge stem cells already carry out roles in cellular
specialization and renewal, which might explain the powerful regeneration capacity of
these living systems [22,23]. In the case of higher organisms, stem cell potency is reduced
over time during specialization [15]. Organ formation in the embryos of these organisms
requires the presence of tissue-specific stem cells, which later give rise to the organ-specific
Figure 1[15,24]. In the adult stages, organ
M.Merino
& Garcia-Sanz
cell hierarchy
driven by growth and patterning signals
architecture and functionality are maintained by somatic stem cells, which are found in
low frequencies in most adult tissues [25–31].
Growth Regulators
Cancer & Size Control
Microbiome & Cancer
Cancer & Cell Competition
Cancer Stem Cells
2001
Cancer Hallmarks
2000
Proto-oncogenes
1980s
Chemicals
Others
Genetics
Cancer Roots
Environment
Figure 1. Cancer roots and growth regulators. Tree chart depicting known origins of cancer (brown),
timeline of key discoveries in cancer research (green), and growth regulators during tumoral growth
(blue).
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Thus, evolution gave rise to multicellular living systems formed by distinct anatomical
structures (i.e., organs) which perform one or more physiological functions. This anatomical
organization is the result of a cellular hierarchy established during development, which
maintains required features through adulthood. As a result of this hierarchy, organ systems
communicate and work together to generate successful living individuals. This setting
seems to be a constructive role of evolution; however, what happens when rebel cells
against the current regulation came up into this setting?
3. Tumoral Growth: From Proto-Oncogenes and Hallmarks of Cancer, to the Cancer
Stem Cell Hypothesis
In certain diseases, whether they occur during development or adulthood, cells within
tissues can take over the existing molecular mechanisms for other purposes. One of
these examples is tumorigenesis. Initial studies in the cancer field showed the role of
proto-oncogenes and oncogenes in tumoral growth [32,33]. Later, in 2OOO, the hallmarks of cancer were discussed by Hanahan and Weinberg, suggesting that most cancers
acquire a similar set of functional capabilities, although by using different molecular mechanisms [34]. These capabilities include, amongst others, (i) limitless replicative potential;
(ii) self-sufficiency in growth signals; (iii) tissue invasion and metastasis; and (iv) evasion of
apoptosis [34,35]. In an attempt to reconcile all of these facts, a new hypothesis explaining
the bases of tumoral growth was subsequently formulated [36]. The cancer stem cell hypothesis suggested that within the tumour, there is a small subpopulation of cells with stem
cell properties, which drive tumoral growth [36]. Cancer stem cells (CSCs) were initially
described in leukaemia, and afterwards in solid tumoral tissues, including mammary gland
and brain tumours [37–39]. Despite the initial controversies on the existence of CSCs, the
presence of CSCs was later demonstrated in in vivo studies [40], which identified CSCs in
adenomas, melanomas, gliomas and mammary gland tumours [41–44] (Figure 1).
4. Tumours as Caricatures of Dysfunctional Organs
Nowadays, it is established that CSCs are at the top of a hierarchy. These cells divide either symmetrically, amplifying the CSC population, or asymmetrically, generating transient
amplifying cells with high proliferative potential and giving rise to more differentiated cell
populations and tumoral heterogeneity. In addition, CSCs are the root of metastasis generation, therapy resistance, and relapse [45–48]. Indeed, some aspects of tumour development
greatly resemble the processes of organ development. CSCs can control tumoral growth
and also have differentiation capacity, generating aberrant organ-like structures which
show reminiscent patterning from the original organs. However, this tumoral patterning is
mostly observed in early cancer stages. Over time and contrary to wild-type organ development, cells within the tumour acquire fewer differentiated traits, somehow showing a
process of organ devolution [48,49]. It is worth mentioning that tumours within a living
individual perform different functions and communicate with other organs [49], though
most of these functions are likely not well aligned with the other organ systems in terms
of organismal survival [49]. Tumour-to-organ communication triggers several systemic
responses, including: suppression of the immune system, coagulation abnormalities, and
changes in metabolism. One striking effect of tumour-to-organ communication is cachexia,
a wasting disorder which causes severe weight loss and fatigue [50,51]. Cachexia directly
causes up to 30% of cancer deaths and is induced by factors secreted by the growing
tumours [49]. Therefore, these systemic tumoral effects are the cause of a high percentage
of cancer deaths, rather than the primary tumoral growth or metastasis itself [49].
5. Cell Competition in Primary and Secondary Cancer Growth
Several studies confirm that tumours can develop from single clones which acquire a
set of mutations driving overgrowth [52,53]. These mutations are of diverse origins: they
can be inherited in the autosomal or mitochondrial DNA, induced by chemical carcinogens
or environmental factors, or modulated by the individual’s microbiome [54–61] (Figure 1).
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Tumours, while growing, increase by volume and thus the contact area with the wild-type
host tissues also increases. At this tumour–wild-type interface, tumoral cells battle against
host cells in order to make “territorial gains”. During this battle, host cells are usually
eliminated from the tissue undergoing apoptosis, and the speed at which the host cells are
eliminated correlates with the tumoral growth rate [41,62–68]. This phenomenology of cell
competition was initially found in Drosophila growing tissue when analysing ribosomal
mutations (i.e., Minute) using genetic mosaics [49]. The so-called unfit cells were eliminated
from the growing organ in the presence of the so-called fit cells [69,70]. Currently, we know
that cell competition principles are conserved from Drosophila to humans, playing multiple
physiological roles during development, adulthood, disease, and ageing [41,62–65,71–86].
In the literature, a great number of studies show that the bases of these competitive
behaviours are of different natures [14,41,62,63,69,71–73,77,81,87–89]. Cells can battle for
growth factors and also space; furthermore, signalling levels and growth rates seem to
play a big role in the game [62,65,69,77,81,87,88,90–99]. For instance, during organ growth
in Drosophila, and in vertebrates, cells with “wrong” morphogen signalling levels are
eliminated from the growing field in order to maintain wild-type size or pattern [87,88,99].
Primary tumoral growth happens within the original tissue/organ where it was
initiated. However, these primary tumoral cells can acquire migratory capabilities in order
to conquer overseas territory. During the metastatic cascade, cancer cells leave the primary
tumour, travel through the bloodstream or lymphatic system, and reach distant organs,
then develop secondary tumoral outgrowth or metastasis [100,101]. Remarkably, tumoral
cells do not metastasize in a random manner. Cancer metastases are selectively distributed
depending on the cancer type and subtype. Some examples of organ-specific metastasis
include the preference of pancreatic and uveal cancers to form metastasis to the liver, while
prostate cancer often metastasizes to bone [100,102–104]. It is shown that some tumours
over-express chemokine receptors, which are functional and therefore trigger the migration
of tumour cells towards the sites where the ligands for the particular receptor expressed in
the tumour cells are synthesized [105]. For instance, tumours expressing the chemokine
receptor CCR9 tend to generate metastasis on the small intestine [105–112].
However, the mechanisms that cancer cells exploit in order to cause secondary overgrowths in targeted organs are largely unknown, and it is still a major open question in the
field [49,100]. A plausible hypothesis is that during the metastatic process, migrating cancer
cells, which carry reminiscent signalling profiles from their original organs, must find a
field that is compatible with their own signalling profile in order to grow. Otherwise, cancer
cells within an incompatible field will be outcompeted and eliminated, a process which we
might call “metastatic competition” (Figure 2A,B). Perhaps, this kind of competition could
also engage spatial constraints from the target field. Actually, this hypothesis is consistent
with the “seed and soil theory” proposed by Stephen Paget in 1889. Paget compared the
migrating cancer cells to seeds which are randomly distributed, but will grow solely in
congenial soil [100,113,114].
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Figure 2.2.Metastatic
MetastaticCompetition
Competitionhypothesis
hypothesisand
andtumoral
tumoral
growth.
(A).
Metastatic
cells
with
difFigure
growth.
(A).
Metastatic
cells
with
differferent
signalling
profiles
(
)
than
the
signalling
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(organ
)
might
ent signalling profiles (≁) than the signalling profiles from the target organs (organi) mighti be outbe outcompeted
and eliminated
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tumoral
thus abolishing
growths.
(B).
competed
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thusfield,
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Metastatic
Metastatic
cells with
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cells
with similar
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and
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(C). Signalling
profiles
and cells
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i and organ
j are depicted in difform metastatic
overgrowths.
(C). Signalling
profiles
and cells
organ
i and organj are depicted in
ferent
colours;
t refers
to time.
different
colours;
t refers
to time.
6. Scaling
Scaling Phenomena
Phenomena during
during Development,
Development, Adulthood,
Adulthood, and
and Tumorigenesis
Tumorigenesis
6.
strikinghow
howdeveloping
developing
systems
remain
proportional
while
growing.
the
ItItisisstriking
systems
remain
proportional
while
growing.
In theIncase
case
of
human
development,
the
size
of
our
hands
scales
with
the
size
of
our
growing
of human development, the size of our hands scales with the size of our growing body.
body. These
proportionalities
already
discussed
ago;however,
however,the
the scaling
scaling
These
proportionalities
were were
already
discussed
longlong
ago;
Cells 2023, 12, 872
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mechanisms were not known [115]. Indeed, during organ growth, these proportionalities
can be controlled by morphogen gradients. Drosophila research has largely contributed
to our understanding of the molecular mechanisms regulating scaling in organ growth.
For instance, in the developing Drosophila wing, the Decapentaplegic (Dpp) morphogen
regulates growth and patterning phenomena [116–123]. Dpp spreads from a source, located
at the centre of the tissue, and forms a concentration gradient into the target cells, which
can be measured by its particular decay length (λ) [116,120,124]. It has been shown that
during wing growth, the λ of the Dpp gradient correlates with the size of the tissue.
That is, the Dpp gradient scales with tissue size [116,120]. To fulfil this job, there is
a mechanism which tunes the λ during organ growth, keeping the gradient and tissue
proportional [87,88,116,125–127]. In this particular organ (i.e., wing), Dpp signalling scaling
failure leads to defects in tissue size and pattern formation [87,88,116,126,128,129].
It is noteworthy that organ scaling happens not only in developing systems, but
also during adulthood. A peculiar scenario is the case of regenerative growth, by which
organisms replace or restore tissues and organs. This mechanism ensures that the final size
of the regenerating tissue or organ remains proportional with morphological patterns of
the adult individual [130,131]. However, throughout evolution, there is loss of regenerative
growth [132]. A second example of this is organ scaling in human adulthood. Several
reports show that organ weight can correlate with total body weight, additionally showing
different means of organ weight between females and males [24,133,134], most probably
due to modulation of the total number of cells per organ, although, the mechanistic bases
of these proportionalities remain unknown. Analogously, the size differences observed
between female and male organs can also be found in tumoral growth. Interestingly, studies
describe that tumour sizes can differ significantly between females and males, exhibiting
bigger tumour sizes in males than females [135–137]. This fact does not appear to be trivial,
and at the moment we might not have a biological explanation for this phenomenon.
7. Concluding Remarks and Future Views
A widespread feature among different cancer types is the association of tumour size
with patient outcomes [138–140]. Generally, bigger tumour sizes correlate with worse
outcomes [138–140]. At present, most clinically used therapeutic drugs target cancer cells
with high proliferation rates; however, CSCs show SC features, including slow proliferation
rates [45,48] and usually they remain unaffected by these drugs. Therefore, treatment-wise,
this becomes a challenging issue: pruning the branches from the mistletoe does not kill the
parasite, perhaps it will make it grow more vigorously instead.
The literature describes the same order of magnitude in the number of cells per
volume within wild-type epithelial tissues and tumours of epithelial origin [141–144]
(~108 cells/cm3 ). An open possibility is to tackle the mechanisms controlling tumour
size. During tumoral growth, different clones of cells are generated, which might reflect
reminiscent patterning cues. Within the tumoral field, as happens during wild-type organ
growth, clones of cells can act as sources of morphogens and other secreted factors, cooperating with each other and thus controlling tumour size [122,126,128,145] (Figure 3A).
Morphogens and other secreted factors can be produced by tumoral cells, secreted, and
spread throughout the tissue [122,126,128,145], then acting in a paracrine fashion on other
cells by regulating growth and pattern formation [122,126,128,145]. In this context, altering the biophysical properties of the tumoral field could be an option to consider for
therapeutic purposes. Hence, by decreasing the range of these secreted factors within the
tumoral field, proliferative rates of cancer cells might decrease, and therefore modulate
tumour growth (Figure 3A,B). Regarding these issues, we expect that future research will
uncover the mechanistic “forces” driving organ growth, which may pave the way to the
implementation of new strategies to impair human tumorigenesis.
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Figure 3.
Clonal cooperation and tumoral growth.
During tumoral growth, different
Figure 3. Clonal cooperation and tumoral growth. During tumoral growth, different clones/subclones/subclones of cancer cells are generated, which can act as secreted factor sources, boostclones of cancer cells are generated, which can act as secreted factor sources, boosting tumoral
ing tumoral growth. The spread of these secreted factors depend on the biophysical properties of the
growth. The spread of these secreted factors depend on the biophysical properties of the tumoral
tumoral
(A). Depicted
plot normalized
showing normalized
secreted
factor concentration
vs. normalized
field.
(A).field.
Depicted
plot showing
secreted factor
concentration
vs. normalized
field pofield
position
within
the
tumoral
field
a.
Different
colours
depict
different
secreted
factors.
sition within the tumoral field a. Different colours depict different secreted factors. TumoralTumoral
field a
field a (tumour
shows
high spreading
biophysical
properties,
increasing
the range
of these
secreted
a), shows
spreading
biophysical
properties,
increasing
the range
of these
secreted
fac(tumour
a ),high
factors
throughout
tumoral
field.
These
to clonal/subclonal
cooperation,
increasing
tors
throughout
the the
tumoral
field.
These
can can
leadlead
to clonal/subclonal
cooperation,
increasing
the
proliferation
of cancer
cellscells
andand
therefore
boosting
tumoral
growth
the proliferation
of cancer
therefore
boosting
tumoral
growthrates
rates(g).
(g).(B).
(B).Depicted
Depictedplot
plot
showing
showingnormalized
normalizedsecreted
secretedfactor
factorconcentration
concentrationvs.
vs.normalized
normalizedfield
fieldposition
positionwithin
withinthe
thetumoral
tumoral
field
fieldb.
b. Different
Differentcolours
coloursdepict
depictdifferent
different secreted
secreted factors.
factors. Tumoral
Tumoralfield
field bb (tumour
(tumourbb) )shows
showslow
low
spreading biophysical properties; thus, secreted factors spread over small ranges within the tumoral
spreading biophysical properties; thus, secreted factors spread over small ranges within the tumoral
field. Small ranges of secreted factors in the tumoral field can abolish clonal cooperation and defield. Small ranges of secreted factors in the tumoral field can abolish clonal cooperation and decrease
crease tumoral growth rates (g). (C). s: refers to the spreading ranges of secreted factors; g: refers to
tumoral
growth
rates
(g).
(C). s:torefers
the
tumoral
growth
rate;
t: refers
time.to the spreading ranges of secreted factors; g: refers to the
tumoral growth rate; t: refers to time.
Author Contributions: Both authors contributed equally to the conceptualization of this work, writing of the manuscript and figure preparation. The authors have read and agreed to the published
version of the manuscript.
Cells 2023, 12, 872
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Author Contributions: Both authors contributed equally to the conceptualization of this work,
writing of the manuscript and figure preparation. All authors have read and agreed to the published
version of the manuscript.
Funding: M.M.M. was supported by Swiss National Science Foundation (SNSF) (SystemsX.ch,
Transition Postdoc Fellowship) and Novartis Foundation Fellowships. The work in JAGS’ laboratory
is supported by the Spanish Ministry of Science and Innovation PID2019-105404RB-I00, financed by
MCIN/AEI/10.13039/501100011033.
Acknowledgments: We apologize to all colleagues whose work we have unintentionally neglected
to cite.
Conflicts of Interest: The authors declare no conflict of interest.
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