ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 1, pp. 19-31 © Pleiades Publishing, Ltd., 2025.
Published in Russian in Biokhimiya, 2025, Vol. 90, No. 1, pp. 22-34.
19
REVIEW
Rethinking the Evolutionary Origin, Function,
and Treatment of Cancer
Anatoly V. Lichtenstein
N.N. Blokhin National Medical Research Centre of Oncology,
Ministry of Health of the Russian Federation, 115478 Moscow, Russia
alicht@mail.ru
Received September 29, 2024
Revised September 29, 2024
Accepted December 8, 2024
Abstract— Despite remarkable progress in basic oncology, practical results remain unsatisfactory. This dis-
crepancy is partly due to the exclusive focus on processes within the cancer cell, which results in a lack of
recognition of cancer as a systemic disease. It is evident that a wise balance is needed between two alternative
methodological approaches: reductionism, which would break down complex phenomena into smaller units
to be studied separately, and holism, which emphasizes the study of complex systems as integrated wholes.
A consistent holistic approach has so far led to the notion of cancer as a special organ, stimulating debate
about its function and evolutionary significance. This article discusses the role of cancer as a mechanism
of purifying selection of the gene pool, the correlation between hereditary and sporadic cancer, the cancer
interactome, and the role of metastasis in a lethal outcome. It is also proposed that neutralizing the cancer
interactome may be a novel treatment strategy.
DOI: 10.1134/S0006297924603575
Keywords: war on cancer, cancer origin, cancer therapy, hallmarks of cancer, phenoptosis, cancer maleficence,
neutralization strategy
In memory of V. P. Skulachev
INTRODUCTION
A recent publication, entitled “Why do Patients
with Cancer Die?” [1], introduces a new “Roadmap
Articles” series, which are intended to set the direc-
tion of the field and stimulate new avenues of thought
and experimentation [2]. The text states that the spe-
cific causes of cancer mortality remain poorly under-
stood, which presents a challenge for the development
of novel treatment strategies. It is hoped that this line
of experimentation will contribute to further advances
in the field of cancer research and enhance clinical
practice.
The same question (“What is the cause of death
in cancer patients?”) had been asked 10 years earlier
as an invitation to discuss the problems of the can-
cer–host relationships not only from a utilitarian-med-
ical, but also from a biological perspective [3]. Indeed,
understanding the mechanism of death may open up
many possibilities for treating cancer by blocking the
various stages of the process, whereas not knowing the
mechanism condemns the physician to the only pos-
sible treatment strategy – physical destruction of the
cancer cell. This is exactly what is happening today,
however complex, difficult, and painful it may be. The
predominant focus of mainstream research on intra-
cellular processes [4], driven by the dominant desire
to find deeply hidden vulnerabilities of the cancer cell,
has led to the emergence of an increasing number of
hallmarks of the cancer cell [5-8], without attempts to
causally link them to the hallmarks of cancer disease
(weakness and weight loss, chronic inflammation,
anorexia, cachexia, anemia, coagulopathy, NETosis,
systemic disorders, multiple organ failure) [9-18].
Today, as 20 years ago, “cancer research tends to fo-
cus on individual cellular mechanisms, almost to the
near exclusion of what is happening in the organism
as a whole” [19]. As a result, despite many remark-
able advances in basic oncology, there is a growing
sense that cancer research is on the verge of a par-
adigm shift [20]: practical advances remain limited,
LICHTENSTEIN20
BIOCHEMISTRY (Moscow) Vol. 90 No. 1 2025
the financial burden of treatment is a major concern,
and despite some achievements in personalized ther-
apy, surgery remains the main hope.
The discrepancy between the progress of exper-
imental and practical cancer research appears to be,
at least in part, a consequence of the triumph of a
reductionist approach, which has resulted in a shift
away from a holistic perspective [21]. (This conflict,
as in the ancient Indian parable of the blind sages
groping the elephant, is that a deep dive into the de-
tails of an object can lead away from understanding
the object as a whole.) The holistic approach calls for
an evolutionary perspective to be applied when ex-
amining the cancer–host relationships, a stance that
is increasingly supported by recent evidence [22].
According to the traditional view, cancer arises as a
consequence of the “design” constraints characteris-
tic of evolution; it is the result of random mutations
that lead to the disruption of multicellular coopera-
tion, and cancer cells behave as “cheaters”, reverting
to their previous single-cell lifestyle [23, 24]. They self-
ishly replicate, compete for survival, spread between
tissues and develop high reproductive success at the
expense of Darwinian host fitness [25-27].
In contrast to the common opinion, two long-stand-
ing articles have presented the scientific community
with an “elephant”, discovering that cancer is in fact
a special organ [28, 29]. Indeed, a tumor meets the
formal definition of an organ as an “anatomically
discrete collection of tissues integrated to perform
specific functions” [28] and has the appropriate attri-
butes– a complex hierarchical structure, often imitat-
ing normal tissue structure [30], the presence of stem
and differentiated cells, regular stages of development,
and integration with body systems. Cancer is extreme-
ly evolutionarily conservative: apparently a product
of multicellularity that emerged about one billion
years ago, it affects the majority of metazoan species
[24, 27, 31].
The concept of “cancer as an organ” represents
a radical departure from the traditional view. But
although the term entered the scientific mainstream
and it was even recognized that the complexity of
tumor organ may exceed that of normal tissues [6],
this paradigm shift went virtually unnoticed. This is
probably because the first crucial step (the recognition
of the fundamentally different nature of cancer than
previously thought) was not followed by the second
necessary and obvious one – a broad discourse on
the function that gave rise to this organ and ensured
its widespread distribution in the animal world (it
is impossible to study an organ in isolation from its
function and outside of an evolutionary perspective).
This study aims to fill this gap in the existing liter-
ature by examining cancer as a mechanism of puri-
fying selection of the gene pool, sporadic cancer as
a by-product of hereditary cancer, and the maleficence
of the cancer cell as its main hallmark. It is also sug-
gested that neutralizing the cancer interactome may
be a new treatment strategy.
EVOLUTIONARY ORIGIN OF CANCER
Early suggestions that cancer fulfils the function
of purifying selection [22, 32-35] have not gained trac-
tion because most of the individuals that are killed
by cancer are post-reproductive [36]. Nevertheless, the
concept of “cancer as an organ” rekindles the debate,
given that each organ must have an evolutionary ra-
tionale for its existence.
There are two types of cancer (hereditary and
sporadic) and only the former is capable of negative
selection. Hereditary cancer is the consequence of a
germinal mutation in one of several dozens of “essen-
tial” genes [34, 37] involved in DNA repair, cell cycle
regulation and cell-death pathways [38]. The germi-
nal driver mutation, present in every cell of the body
(including its germinal cells), represents a significant
risk of cancer in its carrier. There are two main rea-
sons for this: firstly, the cell transformation pathway
is shortened, and secondly, the would-be cancer cell
is initially located in a genetically compromised mi-
croenvironment (a situation that can be described as
“criminal ‘seeds’ in criminogenic ‘soil’” [39]). Thus,
the germinal driver mutation poses a double danger:
to the organism (high risk of highly penetrant, early
onset cancer) and to the species (high probability of
transmission to offspring). However, the realization
of the former possibility eliminates the latter or, as
Steve Sommer put it, “cancer kills the individual and
saves the species” [33]. Inherited cancer syndromes
with Mendelian dominant inheritance sharply reduce
reproductive success of offspring [40] and purify the
gene pool of the population from mutant alleles (fre-
quency of predisposing alleles in population <1%)
[41, 42].
Hereditary cancer is relatively rare [43-51], ac-
counting for only a small fraction (~1%) of cancer
incidence. So, the question arises how to explain the
huge quantitative predominance of sporadic cancer,
which is caused by somatic (not inherited) mutations,
develops over decades and affects mainly people of
post-reproductive age. Indeed, why kill old people
who do not participate in evolution? The answer per-
haps lies in the question itself: cancer kills old people
precisely because they do not participate in evolution.
In the spirit of the concept of antagonistic pleiotropy
[40, 52, 53], one can assume that cancer acts in old
age “by inertia”, i.e., not out of necessity but because
of the impossibility of getting rid of it (an old age
that does not produce offspring is unable to evolve).
EVOLUTIONARY ORIGIN, FUNCTION, AND TREATMENT OF CANCER 21
BIOCHEMISTRY (Moscow) Vol. 90 No. 1 2025
Thus, sporadic cancer is probably a by-product of he-
reditary cancer, and its enormous quantitative prev-
alence in Homo sapiens is a payment for artificially
created comfortable life (with all its excesses and bad
habits), for the constantly growing (~2.5 years per
decade) human life-span due to changes in hygiene,
public health, and nutrition [40], and for the aging-in-
duced decrease in the transformational resistance of
stem cells [54]. The lifetime risk of cancer in countries
with an average life-span of 75-80 years is now ~50%,
while by age 120 years it is predicted to be nearly 90%
for men and over 70% for women [55]. High cancer
incidence is probably a peculiarity of Homo sapiens
that is far from typical representative of the animal
world. In most other mammalian species cancer inci-
dence rates are much lower [27, 56].
To illustrate the difference between hereditary
and sporadic forms, consider the analogy of cancer
with a self-destruction mechanism built into a mis-
sile; being hidden in the norm, it manifests itself in
an accident. It may function as designed, preventing
catastrophic consequences in the very rare events of
a missile failure (hereditary cancer), or it may mal-
function as a result of aging and deterioration of hard-
ware components during storage. The longer the stor-
age, the more frequent the failures (sporadic cancer).
While in the first case the process is initiated by a
small number of pre-determined deviations (and, ac-
cordingly, is realized by a few well-defined scenarios),
in the second case it may result from a complex com-
bination of multiple random defects accumulated over
many years (and, accordingly, be realized in myriad
manifestations). This analogy can explain the peculiar-
ities of the mutational landscapes of hereditary and
sporadic cancers [57-59] as well as many clinical, mor-
phological and molecular differences between them.
The widespread use of NGS for hereditary test-
ing has allowed experimental investigation of geno-
type-phenotype correlations among cancer patients
[60]. Although the phenomenon of purifying selection
by hereditary cancer seems undoubted, its efficacy
has been questioned by recent studies. Contrary to
expectations, it turned out that germline pathogenic
variants (GPVs) in cancer predisposing genes are more
common than anticipated [51, 61, 62]. Over a quarter
of cancers in carriers of GPVs in high-penetrance
genes lacked specific hallmarks of tumorigenesis as-
sociated with the germline allele [58]. This suggested
that the tumors have developed independently of the
underlying pathogenic germline allele and, therefore,
GPVs are less penetrant than previously thought [63].
Several considerations can be made in this re-
gard. First, determining the status of inherited muta-
tions is complicated by the unexpectedly widespread
occurrence of such phenomena as postzygotic mosa-
icism, aberrant clonal expansion, and clonal hemato-
poiesis [47, 64-76], which sometimes lead to misclas-
sification. Second, in studying cancer as a biological
phenomenon, Homo sapiens can hardly be considered
as a representative experimental model. In the animal
kingdom, cancer has a significant impact on the com-
petitive abilities of individuals, susceptibility to patho-
gens, vulnerability to predators, and ability to disperse
[31]. Habitat conditions, in turn, are thought to in-
fluence disease pathogenesis. Thousands of years of
civilization have led to such radical changes in human
lifestyle (hygiene, public health, nutrition) and envi-
ronments that they may have significantly reduced
the selective pressure of hereditary cancer. Third, a
study was carried out recently to assess directly the
evolutionary impact of childhood cancer on the hu-
man gene pool. It was found that pediatric cancer
predisposition syndrome (pCPS) genes are highly con-
strained, indicating strong selective pressure on pCPS
genes. The authors concluded that heritable childhood
cancer leads to natural selection strong enough to sig-
nificantly affect the present-day gene pool [77].
The hypothesis that “cancer kills the individual
and saves the species” [33] leads to a highly counter-
intuitive view of cancer as an altruistic phenomenon.
The basis of biological evolution, according to Darwin,
is individual selection (i.e., selfishness). However,
“perhaps the most remarkable aspect of evolution is
its ability to generate co-operation in a competitive
world” [78]. The contradiction between Darwin’s the-
ory and the abundance of examples of co-operation
and altruism in the wild was resolved a century later
in inclusive fitness, kin selection [79, 80] and “selfish
gene” [81] theories. Although theoretical debates are
still ongoing (see [82-85]), the occurrence of co-opera-
tion and altruism in biological populations is unques-
tionable.
Altruism is most actively discussed in relation
to the phenomenon of aging, starting from the early
ideas of Weismann on programmed aging and ending
with the concept of programmed and altruistic aging
by Skulachev and others [86]. Within the latter, the
concept of phenoptosis (the death of a whole organ-
ism) has been put forward. Similarly to cells from
multicellular animals that have the capacity to acti-
vate a program of self-destruction (apoptosis) [87], it
was suggested that “complex biological systems are
equipped with programs that eliminate portions of the
system that become dangerous or unnecessary for the
system as a whole” [88]. One can suggest that cancer
is a special case of phenoptosis. At the level of a mul-
ticellular organism, apoptosis counteracts the spread
of essentially dangerous defects, but at the level of a
population, cancer does this job. It is proposed that
apoptosis and cancer are the first and second lines
of defense of the biological hierarchy against harmful
genetic damages.
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BIOCHEMISTRY (Moscow) Vol. 90 No. 1 2025
DRIVER MUTATIONS TRIGGER
A PRE-EXISTING EPIGENETIC PROGRAM
It is widely believed that cancer results from the
accumulation of driver mutations and that it is as ir-
reversible as the mutations themselves. While in the
vast majority of cases, cancer is indeed preceded by
mutations, they are not absolutely required for tumor
formation. Tumor types with few or no mutations are
known [89], while tumor reversion can occur despite
their occurrence [90, 91]. It was established that epi-
genetic reprogramming itself can drive tumorigenesis
[92] and that reversible inhibition of a gene-silencing
mechanism mediated by Polycomb group proteins can
by itself lead to irreversible tumor formation in fruit
flies [93]. These facts are consistent with the idea of
cancer as a change in normal cell differentiation [94].
In light of Waddington’s epigenetic landscape concept,
mutations of some essential genes cause epigenetic
reprogramming, leading to a critical transition from
the attractor state of a normal cell to the attractor
state of a cancer cell [91]. In support of this view, the
functional analysis of genetic alterations in several
cancers (breast, colon, pancreatic cancer, and glioblas-
toma) showed that driver mutations varying widely
between different cancer types hit the same major
signaling pathways [95].
The latest data prompt a reconsideration of the
role of mutations in carcinogenesis. In contrast with
the prevailing view, it would appear that they are not
the drivers of the stochastic process. Rather, they seem
to act as the trigger for a pre-existing evolutionary
conserved epigenetic program. The evident similarity
between embryogenesis and tumorigenesis suggests
oncofetal reprogramming that enable tumor cells to
escape from immune responses, promote growth and
metastasis [96]. The concept of driver mutations as a
trigger for a conserved program of cancer trans-differ-
entiation may reconcile the conflicting Somatic Mu-
tation Theory (SMT) [97] that views cancer as a ge-
netic cell-based disease, and the Tissue Organization
Field Theory (TOFT) [98, 99] that posits cancer as a
tissue-based disease caused by developmental errors.
CANCER AS A PROGRAMMED DEATH
OF AN ORGANISM
Cancer as an organ must have a function, and it
is obvious – it is killer function, which is realized in
a step-by-step manner and has the features of pro-
grammed death of the organism [35, 100]. The term
“cancerous transformation” denotes a more profound
alteration than the mere acquisition of a number of
phenotypic characteristics, such as unregulated cell
division. It signifies a radical change in the social be-
havior of a cell, whereby a “creator” cell becomes a
“destroyer” cell. If a normal cell maintains the homeo-
stasis of the organism, a cancer cell, on the contrary,
like a “zombie”, subordinates the host’s metabolism to
its own needs [101], builds a “niche” [102, 103], pro-
vides itself with blood supply [104], energy supply
[105] and innervation [8, 106, 107], forms a microen-
vironment and pre-metastatic niches [108-112], colo-
nizes the organism [113] and, finally, kills it and itself.
Death of cancer patient is perceived as something
so obvious, self-evident, and inherent to cancer that
the killer function is not explicitly articulated, not
given due attention and is absent from the current
list of hallmarks of cancer. The conventional wisdom
that cancer mortality is usually a consequence of me-
tastasizing equates metastasizing with maleficence, i.e.
the ability of a cancer cell to kill the organism (the
term maleficence is used here to distinguish it from
malignancy, commonly denoting malignant growth as
a whole). It is obvious, however, that metastasizing and
maleficence are properties that, although apparently
closely related, are essentially different. The fact that
the NALCN gene regulates non-malignant cell dissem-
ination, divorcing metastasizing from tumorigenesis,
is significant in this regard [114]. There is much evi-
dence of the systemic changes that cause most cancer
deaths, not metastases per se [1, 29, 115].
The maleficence seems to be precisely the “hall-
mark waiting to be recognized” [116] that establishes
the functional link between tumor and host and to
which all other hallmarks apparently play an auxilia-
ry role. Cancer maleficence has a diverse toolbox that
includes secreted factors, extracellular microvesicles,
extracellular nucleic acids and neurogenic factors [8,
101, 117-133]; this arsenal, which can be termed the
cancer interactome, is capable of affecting distant or-
gans, causing various paraneoplastic syndromes [9-13,
101, 134-136]. It is clear that the interactomes of nor-
mal and cancer cells are essentially the same, since
they share the same genome. Apparently, the process-
es that a normal cell uses to maintain homeostasis,
a cancer cell directs, on the contrary, to homeostasis
failure, leveraging them inadequately in time and/
or place, in unacceptable concentrations and/or com-
binations. One such “dual-use” facility is the senes-
cence-associated secretory phenotype (SASP), which is
known to be a potent tumor suppressive mechanism
in normal ageing, but also a pro-malignant factor in
genotoxic stress-induced cells [121, 137, 138]. Perhaps
the most significant component of cancer malefi-
cence is chronic inflammation, which often precedes
and always accompanies malignant transformation
[96, 139-145]. As a fundamental protective mecha-
nism designed to fight infections and heal wounds,
“it is antagonistic to the homeostatic mechanisms of
organism, thus accounting for inevitable disturbance
EVOLUTIONARY ORIGIN, FUNCTION, AND TREATMENT OF CANCER 23
BIOCHEMISTRY (Moscow) Vol. 90 No. 1 2025
of many functions” [146]. Recently, the involvement
of extracellular vesicle fusion with target cells in trig-
gering systemic inflammation has been shown [147].
One of consequences of inflammation is neutrophil ex-
tracellular traps (NETs), a normal defense mechanism
designed to trap and neutralize microbes, but capa-
ble, when chronically activated, of inducing multi-or-
gan failure [17, 148-152]. Cachexia is also closely
linked to the inflammatory process [153-155]. Re-
cently, the involvement of the peripheral and central
nervous system in the oncological process has been
identified [8, 156-158].
NEUTRALIZATION OF CANCER INTERACTOME
AS A TREATMENT STRATEGY
If cancer is viewed as a distinct organ, its de-
velopment as a series of pre-determined events, and
its lethal outcome as a result of specific maleficence,
then an understanding of the unifying mechanism of
this function is an essential prerequisite for the de-
velopment of a successful treatment. The commonly
accepted statement “cancer is not one, but many dif-
ferent diseases”, which states the enormous variety
of clinical manifestations of cancer, reflects the clini-
cal point of view. However, the experimenter sees in
this diversity a single, albeit multivariant, pathogenic
mechanism.
Progress in the war on cancer is unsatisfactory
for two main reasons. Firstly, cancer cells quickly
learn to avoid the means of defeat and, after initial,
often very significant losses, regain their former po-
sitions and go on the offensive [159]. Secondly, the
essential relatedness of cancer and normal cells makes
the treatment a form of “friendly fire” with attendant,
sometimes unacceptable, losses. This situation prompts
to consider alternatives to current cancer cell-killing
approaches, such as adaptive therapy [160, 161], “dis-
ease tolerance as a defense” strategy [162, 163], can-
cer reversion strategy [91], and neutralization strate-
gy based on “antidotes” rather than “poisons” [164].
In the latter case, it is proposed that military actions
be reoriented from the organ itself to its function, or
more specifically, to the cancer interactome. It is this
“neutralization” strategy that humans employ in the
fight against their external enemies (poisonous ani-
mals): instead of hopeless and disastrous attempts
at total destruction of the animals themselves, effec-
tive and harmless poison-specific antidotes are used.
Presumably, the cancer interactome-neutralizing strat-
egy could have several advantages over the cancer-
killing strategy: (i) it seems likely that such a treat-
ment would be considerably less toxic; (ii) assuming
that different cancers have a similar interactome, the
cancer neutralization strategy can be reduced to a
limited number of therapeutic procedures instead of
extremely expensive individualized therapy; (iii) the
cancer-neutralizing strategy could also find appli-
cation in chemoprevention, which uses pharmaco-
logical agents to arrest carcinogenesis at its earliest
stages [165]. Some known examples of neutralizing
strategy include the use of non-steroidal anti-inflam-
matory drugs (NSAIDs) to ameliorate the symptoms
and improve the well-being of cancer patients [166]
and DNase I injections into experimental animals to
inhibit NETosis-associated metastasis [148].
To develop an effective antidote, a detailed un-
derstanding of the mechanism of harmful action is re-
quired. In the case of cancer, this means thorough in-
vestigation of interactome-mediated interplay between
tumor and distant tissues. It is of great importance
to ascertain the degree of variability and specificity
of both the cancer interactome itself and its tissue
and metabolic targets. In this context, it is instruc-
tive to look at the experience of aging studies, which
focus on the aging organism as a whole and use the
full range of high-throughput ‘omics’ technologies to
study molecular processes in different tissues at the
genomic, epigenomic, transcriptomic, proteomic, and
metabolomic levels [167-169]. It can be assumed that,
as in the case of aging, where the insights gained have
led to significant practical results [170], the holistic
approach to the cancer-bearing organism will reveal
the targetable vulnerabilities in the cancer maleficence.
Funding. This study was funded by N. N. Blokhin
National Medical Research Center of Oncology.
Ethics approval and consent to participate.
This work does not contain any studies involving hu-
man and animal subjects.
Conflict of interest. The author of this work de-
clares that he has no conflict of interest.
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