Medical Hypotheses 144 (2020) 110240

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Cell functioning in norm and pathology in terms of the activity paradigm: T

Oncogenesis
Andrey A. Venerina, Yana A. Venerinaa, , Yury I. Alexandrovb,c,1
⁎

a
I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
b
Shvyrkov’s Lab, Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
c
Department of Psychology, National Research University Higher School of Economics, Moscow, Russia

ARTICLE INFO ABSTRACT

Keywords: Over the past years many theories of carcinogenesis have been developed. Nowadays, there are two prevalent
Carcinogenesis theories of carcinogenesis – two-hit hypothesis, which considers mutations as the main factor in malignization
Cells’ activity and tissue hypothesis, which considers tissue homeostasis disruption for providing cells transformation. Both of
The activity paradigm these theories explain cancer origin basing on principles of the reactivity paradigm. This paradigm emphasizes
Systemogenesis
role of different stimuli in malignization. However, this approach does not provide us with sufficient support in
Goal-directed activity
progress towards either understanding of cancer origin or effective treatment strategies.
In contrast to the reactivity paradigm, we intend to explain oncogenesis within the activity paradigm. Upon
this approach, cells’ activity is goal-directed and is determined by a future event – the adaptive result. The
adaptive result is a proper interaction between the cell and its environment, which provides the cell with re­
quired metabolites. To achieve this result cells have to cooperate with each other and synchronize their needs. If
cells fail to satisfy their metabolic ‘needs’ they have to reorganize their activity. This results in morpho-func­
tional restructuring of cells. Summing up, we consider carcinogenesis to be a part of goal-directed adaptive
activity of cells. Morphological and genetic atypia of cancer cells is a variant reorganization of cells’ activity.
Consequently, for better treatment, we should bring both transforming cells and their microenvironment to a
novel cooperation and reorganization of their activity.

Introduction methodological approach. Then we introduce the activity paradigm. It

In the past, many researches have been focused on etiology of
cancer. Many theories of malignancy occurrence have been provided
[1]. Every theory focuses on a new etiological factor, which is con­
sidered to be the main cause of malignization. Nevertheless, neither
theory gives a comprehensive explanation of cancer origins.
After detailed analysis, it becomes obvious that most theories have
the same viewpoint on cells functioning. They consider cells to be just a
passive substrate under influence of different factors. Such interactions
simply go in classical reactivity paradigm. However, such principles
bring us neither to effective treatment strategies, nor to explanations of
cancer origin.
In this article, we attempt to overview the well known facts via
another system of views – the activity paradigm. Before our discussion,
we describe the traditional view on cancer origin with emphasis on its
is our firm belief that contrasting of two fundamental approaches
provides us with a better understanding of oncogenesis.
Nowadays, there are two competing theories of cancer in classical
science. The main point of controversy is the organizational level of
cancer. While some researchers believe that cancer is a cellular pa­
thology; others consider it to be a tissue pathology [2]. However, both
of these theories are based on the same methodology of research.
Theories of cancer
Cancer as a cellular pathology
Cancer arises from the accumulation of somatic mutations and
epigenetic modifications of DNA [3–5]. This hypothesis suggested by
Alfred Knudson is widely recognized as two-hit hypothesis [3,6]. Upon

Corresponding author.
⁎

E-mail address: yana.venerina@gmail.com (Y.A. Venerina).

1
Financial support: article preparation was performed within the state assignment of Ministry of Science and Higher Education of Russia (#0159-2020-0001,
Institute of Psychology, RAS).

https://doi.org/10.1016/j.mehy.2020.110240
Received 14 July 2020; Received in revised form 9 August 2020; Accepted 30 August 2020
Available online 05 September 2020
0306-9877/ © 2020 Elsevier Ltd. All rights reserved.
A.A. Venerin, et al.
this theory, genetic mutations lead cells to malignancy [7]. The de­
velopment of molecular biology in recent years has allowed us to de­
termine a variety of proto-oncogenes and tumor suppressor genes,
which are involved in malignization by changing of their expression
[3].
Factors, which induce DNA damage, are well known. In particular,
radiation exposure may induce genomic instability [8–10]. Genomic
instability may lead to various chromosomal alterations and initiate
cancer [11]. The molecular basis of these alterations is described in
details elsewhere [11–12].
Furthermore, chemical agents have been shown to damage the DNA
structure and cause mutations that provide cells with malignant
transformation [1]. First scientific and practical justification of the
chemical hypothesis of cancer origin appeared in the middle of the 18th
century. As early as in 1775, Percivall Pott reported long-term exposure
of soot as a cause for oncology in chimney-sweeps [1,13]. Since then,
many chemicals have been identified as potential carcinogens [14].
Biological factors may also initiate cancer. The so-called viral theory
of Lev Zilber, based on fundamentals suggested by Ilya Mechnikov in
1910, expected viruses to play the crucial role in triggering of malig­
nant transformations of cells by fusion of viral DNA into DNA of the
target cell [15–17]. Afterwards, oncogenic characteristics of the human
papillomavirus [18–19], the human gammaherpesvirus 4 [18,20–21],
the hepatitis B and C viruses [18,20,22] and the human T-lymphotropic
virus [18,20] were scientifically proved.
In the past years, notions about a role of the immune system in
oncogenesis have extended our understanding of carcinogenesis. It has
been proved that chronic inflammation may lead to DNA damage
[23–25]. In 1853, Rudolf Virchow spotted leukocytes in malignant
tissues and suggested that cancer originates from chronic inflammation
caused by constant tissue damage [23–26]. Subsequently, in 1882,
Virchow’s proponent, Julius Conheim, hypothesized that malignancy
arises from dormant embryonic cells, which start to proliferate under
the activity of various factors [17,27–28].
It is important to note from this point of view that the cell is a
substrate, which is exposed to the factors stated above. All of them have
the potential to influence the cells’ genome to initiate malignization.
Cancer as a tissue pathology
An alternative theory suggests that cancer is a tissue-based pa­
thology [25,29–30]. According to this theory, tumor initiation needs
certain permissive environmental conditions [30]. Tissue homeostasis
realizes control over cells activity [25,29–31]. Similar to cell-based
theories, the disruption of tissue homeostasis by various factors may
result in a loss of control over cells thus contributing to further ma­
lignization [25,29–31].
The reactivity paradigm
Despite the diversity of theories, mentioned above, they are created
by the same methodological approach. Cell-based as well as tissue-
based theories share the attempt to find out some trigger factors, which
lead to cell and tissue transformation.
Such rather reductionist approaches are widely spread in medicine
and have taken root due to Pasteur’s studies of etiological origin of
infectious diseases and also due to Descartes and I.P. Pavlov and many
others, who developed the reflex theory. It is important to note in this
context that the reflex theory considers a reflex as a major mechanism
underlying a variety of physiological processes. Altogether, such per­
ceptions of organismic activity, development of the pathological pro­
cess, as well as organization of behavior can be merged in a consistent
framework, called the reactivity paradigm.
However, such paradigm put constraints to line of scientific rea­
soning, reducing it to a “stimulus-reaction” approach and attempts to
determine an etiological factor. Etiological factor means an external or
2
Medical Hypotheses 144 (2020) 110240
internal factor, inductor of pathway of pathological or normal reactions
targeted towards elimination or adaptation to some aggressive affec­
tion. It leads to a necessity to pay attention only to events prior to
pathological processes, to look for an etiological factor and to disregard
an initial state of the system and needs of organism and cells.
In other words, fundamental oncology, basing on above-described
methodological approaches, typifies cells and tissues as substrate for
etiological factors exposure, where factors are considered to be stimuli,
causing malignization. Nevertheless, Soviet pathologist I.V.
Davidovskiy mentioned that “…no factor itself can be reason of pa­
thology; such reason is always an attitude of the organism to this factor
and vice versa” ([32], p. 17). Thereby, the analysis of etiology of on­
cological processes in the framework of ‘stimulus-reaction’ approaches
causes limitation, i.e. a concentration of attention on the character of
stimuli as well as on the sequence of following alterations leading to
neglecting the fact that the environment is functionally connected to
the organism [33]. That means that perceptions of univocal causality
based on the reactivity paradigm is not theoretically approved, which
may have an impact on clinical medicine leading to an agreement of
opinions about pathogenesis of tumors, cancer recurrence and sponta­
neous regressions [34–35].
Sonnenschein and Soto point out the importance of not considering
cells as “…passive, inanimate things on which one has to act upon
(stimulate) in order for them to proliferate or to move” [36]. Results of
their research demonstrates an inability of reductionist approach to
explain events, which take place during carcinogenesis [2]. They are
developing the tissue organization field theory that regards carcino­
genesis as a “relational problem” [2]. Phenomenological observation
gives them an opportunity to criticize the reactivity paradigm, and re­
quires another scientific approach.
We hereby describe carcinogenesis in the framework of the activity
paradigm. In our opinion, it gives an opportunity to interpret the well-
known facts from another point of view and formulate an alternative
conception of oncogenesis.
The activity paradigm
In the framework of theory of functional systems (TFS), suggested
by Anokhin, activity of the biological system is determined not by a
previous event, as it is in the reactivity paradigm, but by a future event -
an adaptive result. ‘Result’ should be understood as such relation to
environment, which supports survival of the system [37]. Whereas
system is a “…dynamic organization of activity of components with
different anatomical localization, where interaction becomes a mutual
facilitation in the process of ensuring an adaptive for an organism re­
sult” ([38], p. 2). In other words, system organization is a goal-directed
process, aimed at an adaptive result achievement [37,39–41].
Further development of TFS results in creation of the system-evo­
lutionary approach by V. B. Shvyrkov and his research fellows
[38–39,42]. Extrapolation of this approach to the cellular level has led
to the understanding that cells should be considered as ‘an organism
inside an organism’. In the middle of 20th century, Sherrington wrote:
“…To declare that of the component cells which go to make us up, each
one is individual self-centered life, is no mere phrase. The cell is a
component of the body is not only a visibly demarcated unit but a unit-
life. It leads its own life. Each cell is an organized life-system centered
upon itself… The cell is a unit-life and our life which in its turn is a
unitary life consists utterly of the cell-lives“ ([43], pp. 73–74). Thus,
each cell realizes its own genetic programme and actively interacts with
environment to get some vital metabolites [38–39,41]. To satisfy their
metabolic needs, cells have to join with other elements of organism,
forming functional systems [38]. Such cooperation supports cells in
achieving adaptive results in terms of optimal interaction between the
whole organism and environment [38].
If this goal is not achieved, cells have to reorganize their activity
and to create a novel system. Thus, cell activity targets to elimination of
A.A. Venerin, et al.
mismatches between its needs and its current microenvironment by
systemogenesis, which includes extraction of previous experience, self-
organization of cells activity and synchronization of their needs
[41,37–39]. Within the systemic approach, the individual development
of an organism as well as of a cell is a chain of systemogenesis aimed to
afford novel interaction with environment [38].
In several studies it was revealed that systemogenesis is accom­
panied by “early genes” expression and occurs in early ontogenesis as
well as in adulthood or during stress situations [41–42]. In particular, it
was demonstrated that changes in neural microenvironment cause early
genes expression [41–42]. Expression of early genes is followed by “late
genes” expression and causes morphologic and molecular-genetic re­
structuring [41–42]. K.V. Anokhin, Y. I. Alexandrov and coauthors
showed neural expression of c-fos, c-jun and ZENK genes in organisms
facing the necessity to form new principles of behaviour
[41–42,44–45]. They point out that stated above genes’ expression is
required for neural morpho-functional restructuring aimed to adapt to
new environmental conditions [41–42,44–46].
Summing up, the activity paradigm postulates: cells have their own
metabolic requirements, which can be ensured by cells’ activity. If cells
fail to achieve their needs, they change themselves by restructuring and
systemogenesis with extracting their previous individual experience
[41–42].
It is necessary to point out that restructuring of cancer cells affect
genes responsible for proliferation and development in early ontogen­
esis [47–48]. As it is described within the reactivity paradigm, these
genes are active only during cell differentiation and stay inactivated in
adult, differentiated cells; nevertheless, they start to express in cancer
cells under exposure to diverse factors. Such reasoning, however,
cannot bring us to an explanation of systematically repeating genetic
and epigenetic modifications, which anyway lead cells to getting the
same malignant qualities such as the ability to proliferate, resistance to
apoptosis, ability to metastasize, etc. Importantly, all of these qualities
are intrinsic for cells in early stages of ontogenesis. It is revealed that
trophoblastic cells demonstrate high telomerase and apoptotic-inhibitor
survivin activity, as well as cancer cells [49]. Moreover, pathways un­
derlying cell migration during embryogenesis are the same as those
underlying metastasize [50–51]. Overall, it seems to be true that
“…Cancer cells’ phenotype is normal, contrary to the time and place of
its expression” ([25], pp. 49–50).
The oneness of normality and pathology
It seems to be important to discuss, what is normality and pathology
within the activity paradigm. Throughout decades, scientists hesitate
about a border between normality and pathology. I.V. Davidovskiy
pointed out the oneness of what is “physiological” and what is “pa­
thological”: “…the matter is that concept of disease is inseparably
connected to idea of incessant adaptation of an organism to the en­
vironmental conditions. The intensity of these adaptations can overstep
the borders of normal physiology and then these processes, which are
still compensatory, look like unusual, not normal, like pathological.
That is why the disorder, as S.P. Botkin once said, - is “legal phenom­
enon”, because these adaptations have appeared with the first signs of
life on Earth. ([32], p. 14).
Thereby, within the activity paradigm these “adaptive processes”
are systemogenesis, in fact. Actually, the first stage of pathological
process is a particular case of failure to achieve an adaptive result. On
the cellular level, it is a mismatch between cell’s requirements and its
microenvironment. In the activity paradigm, there are not any borders
between normality and pathology. The failure of cells to satisfy their
needs by current interaction with the environment, results in a re­
organization of their activity. Consequently, process, which is con­
sidered to be pathological in the traditional paradigm, reflects sys­
temogenesis in the activity paradigm.
Formation of a new system itself, affects all levels of cellular
3
Medical Hypotheses 144 (2020) 110240
organization, including the morphological one. Soviet and Russian
pathomorphologist G.G. Avtandilov once mentioned, that “every pa­
thological process forms a new system with a unique own structure”
([52], pp. 66–67). It is necessary to understand, that systemogenesis has
the same basis both in ‘normality’ and in ‘pathology’. We appreciate
what I.V. Davidovskiy said: “…there is no pathologic process, which
doesn’t have its prototype in norm” ([32], pp. 18 – 20; [41,42]).
Let us describe such prototypical processes. Analysis of pleiotropic
properties of proteins, which act in neuroplasticity as well as in neu­
ropathology, brings us to a better understanding of the oneness of the
molecular basis of these processes [53].
Several researches show that the molecular basis for epithelial-me­
senchymal transition (EMT) during epithelial carcinogenesis is the same
as that during embryogenesis. Both of these processes employ such
pathways as Wnt, Notch, Hedgehog, TGFb (transforming growth factor
beta) [54,49–51]. It is well known that EMT plays a crucial role in
embryogenesis and development [49,54–55]. In particular, gastrulation
and angiogenesis are based on EMT [31,49]. While EMT, cells lose in­
tercellular junctions and become able to migrate [56]. This opportunity
is important for migration searching activity in anlage and development
of neural crest, axons formation and angiogenesis [50]. In adulthood,
EMT takes place in chronic inflammation areas. Inter alia, it is de­
monstrated that glomerular and tubular epithelial cells transform into
fibroblasts after noci-influence [49,56–58]. It is considered to be one of
the ways to fibrosis as well as to tissue reparation [49,56–58]. Thereby,
EMT can be interpreted as a mechanism underlying system re­
organization.
Furthermore, the Warburg effect - is an evidence that cancer cells
are able to metabolize huge amounts of glucose with its further fer­
mentation to lactate in conditions of sufficient oxygenation and func­
tional sufficiency of mitochondria [59–61]. Glycolysis is known to be
used by embryonic cells in order to overcome hypoxia in the preimplant
stage of embryogenesis [61]. At the same time, mature cells prefer to
use oxidative phosphorylation in conditions of sufficient oxygen level.
Demetrius and coauthors consider the Warburg effect as a necessary
adaptation of a certain clone of cells, which tries to survive in condi­
tions of limited nutrients [60]. If amount and diversity of nutrients are
sufficient, cells using oxidative phosphorylation survive better [60]. On
the contrary, if nutrients are limited, cells using a more simple way of
glucose metabolization, i.e. glycolysis, have a competitive advantage
and grow better [60]. An opportunity to choose the way of glucose
metabolization allows cells to survive. In that way, prevalence of one or
another way of ATP synthesis is a result not of an environmental im­
pact, but cells’ activity to achieve their metabolic needs in such kind of
environment.
Genetic recombination occurs in physical well-being and is neces­
sary for sufficient adaptation and survival of an organism. In particular,
genes of variable regions of human antibody molecules do not exist in
reproductive cells of mammals [62–64]. They form during ontogenesis
by directed site-specific gene rearrangement [62–64] and allows B-
lymphocytes to interact efficiently with environment.
C-fos expression in cancer cells is an important phenomenon. It is
suggested that c-fos expression can initiate malignization [65]. How­
ever, taking into consideration data about c-fos expression during the
embryofetal period in the placenta [66], in cancer cells [65] as well as
in neurons during learning, which is a particular case of systemogenesis
[44], does not allow us to reduce its meaning only to malignization.
From our viewpoint, epigenetic modification, which contributes to c-fos
expression, is not a result of a disruption. Rather, it is a result, required
by cells that need to be reorganized by differentiation, malignization or
another kind of transformation in order to get adapted to environ­
mental changes. It is necessary to note that ‘environmental changes’
should be understood as all clinically justified stimuli of pathologic
processes and adaptive reactions [67]. Thereby, we should emphasize
that changes in cell activity do not depend on factors themselves. Ra­
ther, cell’s activity depends on its choice of behavioral strategy, basing
A.A. Venerin, et al.
on its genetic potential. Summing up, malignization should be con­
sidered as systemogenesis, just one of multiple ways towards adaptation
[32,37,42,68–69].
Local metabolic interaction
It is important to discuss interaction between microbiome and the
whole organism in order to analyze adaptive behaviour of cells. It is
common knowledge that cells not only compete with each other but
also cooperate with each other for the benefit of the whole system
[70–72]. It is shown that functional specialization of bacteria is un­
derlying by genotypic and phenotypic heterogeneity in a single species
and is determined by needs of the population [71–72]. In that way, the
functional system is realized through cooperation of cells, which sup­
port each other to achieve an adaptive result. It can be exemplified by
metabolic integration of microbiome and macroorganism. Such kind of
interaction includes cooperation of cells of the organism with bacterial
cells. This principle is fair while it is profitable for all cells. However, if
the cooperation is less profitable than separate and egoistic existence,
symbiosis gets destroyed. Disintegration of bacteria and cells of the
macroorganism is accompanied by the formation of a novel type of cells
interaction or, in other words, local systemogenesis. The same situation
is observed when serious injuries, blood loss or massive tissue damages
of any genesis occur. In that case, the symbiosis destruction leads to
competition between macro- and microsystems for the substrates,
which results in sepsis and multiple organ failure [73–74]. If coopera­
tion among cells turns out to be less profitable for them than formation
of local metabolic interaction, they start to reorganize themselves.
Probably such evidence of local interaction underlies malignization.
Regarding local interaction, it is interesting to mention organotropic
metastases, which have been widely discussed in the last few years
[75–77]. Steinblicher et al. specifies “…that the side of metastasis is not
chosen randomly but is a rather a consequence of intricate tumor-
stroma interaction in the host organ” ([75], p. 6) and special molecular
mechanisms of how tumors prepare favorable microenvironment for
metastatic promotion are described [76]. One of the identified me­
chanisms of pre-metastatic niche preparation is exosome-mediated in­
tercellular communication [77]. Tumor-derived exosomes contain
several oncogenic proteins and signaling molecules, which accompany
metabolic and immune changes in a chosen tissue, creating conditions
for metastases invasion [76,78–81]. According to the activity paradigm,
niche preparation can be interpreted as activity of tumor cells, directed
to achieving their metabolic needs. This suggestion allows or even
forces us to analyze metastatic disease as a complicated metabolic-
conditioned activity and turns us to the next questions: why do tumors
need metastases and how can we prevent niche preparation?
Future directions
Li and Simon discuss metabolic cooperation between cancer cells
and their microenvironment paying special attention to the competitive
aspect of this interaction and to the accompanying immunosuppression
[76]. In this consideration local tumor microenvironment is observed
and local therapeutic intervention is supposed. It is important to note
that cooperation of cells provides survival of the whole organism. Ac­
cording to the ideas stated above, cooperation of metabolisms of cells of
the whole organism results in achievement of needs for each cell (r; see
Fig. 1) and achievement of the whole organism of proper interaction
with the environment. This joint activity leads to the satisfaction of
cells’ “egoistic” needs as well as needs of the whole organism. Speaking
about cancer, this logic seems to be disrupted and competition starts to
prevail over cooperation.
It is well known, that apoptosis, which plays a crucial role in de­
velopment and survival, is also disrupted in cancer cells [3,30,51];
search ways of cancer cells’ apoptosis intensification is one of the
strategies of cancer therapy. In norm cells can sacrifice themselves for
4
Medical Hypotheses 144 (2020) 110240
survival of others with the same genome by apoptosis or “altruistic
suicide” [82–85]. However, immunosuppression provides survival of
cancer cells but not the organism and its cells.
Conception of the whole-organism mutual cooperation of metabolic
activity of cells and the activity paradigm results in understanding of
necessity of the whole-organism metabolic cells’ cooperation surveys as
well as researches of local metabolic cells’ cooperation. Such approach
suggests special experiments with animals’ usage for exploration of
metabolic integration changes in cancer cells and in intact cells in dif­
ferent types of behaviour. In several studies, it was demonstrated that
activity of neurons as well as activity of co-organized with neurons cells
of other tissues (cells of heart, lungs, etc.) changes while passing from
one whole-organism result’s achievement to another (see Fig. 1), for
example, while switching from approach behaviour to withdrawal be­
haviour or from cognitive workload to motor workload [86–89]. It is
important to note, that dynamics of activity of cells with different
anatomical localization was always cooperated but in different ways
(see Fig. 1). Consequently, interaction between cancer cells and other
cells (including metabolic interactions) may dramatically differ and
change while switching from one behaviour to another because cancer
cells have to interact with different sets and different patterns of ac­
tivity of other cells in mentioned behaviours. In that way, such ex­
periments may help to realize how metabolic state of cancer cells
changes due to the type of behaviour.
According to the statements mentioned above, recent data about
significant positive effect of brief physical workload on cancer-related
cognitive impairment in patients with breast cancer [90] can be con­
sidered as indirect proof of that tumor microenvironment can change as
well as state of the whole organism depending on type of behaviour.
Authors associate positive effect of physical workload with reductions
in cancer-related morbidity and recurrence and consider increasing of
neurogenesis caused by increased concentrations of circulating brain-
derived neurotrophic factor, endothelial growth factor, and insulin-like
growth factor as possible biological mechanism of described effects
[90].
If our prediction is correct, next stage of experiments may be aimed
at investigation of effects and their optimal combination of local –
medicamentous and “global” - behavioural influence on cancer cells.
Results of such experiments may provide choice of effective compre­
hensive curative procedures.
Summary
Genetic mutations along with epigenetic modifications and mor­
phologic changes are considered to be the main factors in maligniza­
tion. However, the activity paradigm without denying the importance
of these factors turns us to a significantly different viewpoint. We
postulate that cells’ activity is result-directed. In that way, cell is con­
sidered to have its own metabolic needs and to organize its activity to
achieve these needs, which are proper interactions with the environ­
ment. Such activity results in cooperation among cells, which forms,
while systemogenesis. Consequently, oncogenesis is a particular mani­
festation of systemogenesis characterized by goal-directed reorganiza­
tion of cells activity, which is supported by “early genes” expression on
primary stages. Term “malignization” describes adaptive processes,
which engage mechanisms of genes activation and morphofunctional
reorganization. Treatment, which is now considered as etiotropic, in
fact is a symptomatic one. To make treatment etiotropic, we should
start from revealing the needs that cells do not achieve by their ‘normal’
activity and to which properties of environment they adapt. It is also
important to note how cancer cells get proper needs; in that case,
analysis of metastases within the activity paradigm may lead to de­
velopment of abilities to control and correct this process. Furthermore,
whole-organism metabolic activity of cells should be taken into con­
sideration as well as local metabolic cells’ cooperation while developing
new curative strategies. In other words, treatment should be aimed at
A.A. Venerin, et al. Medical Hypotheses 144 (2020) 110240

Fig. 1. Changes of metabolic cooperation of cells

related to the whole-organism result. a. Achieving
the whole-organism result 1 (oR1) via coopera­
tion of non-cancer cells. b. Achieving the whole-
organism result 1 (oR1c) via another set of in­
volved cells with their pattern of activity and in­
tegration of cancer cells’ metabolism (mr3). c.
Achieving the whole-organism result 2 (oR2c) via
another set of involved cells with their
pattern of activity and integration of cancer
cells’ metabolism (mr3). Legend:
= non-cancer cells;

= cancer cells; = me­

tabolic results; = metabo­
lism; -not enough experimental
data about cooperation; -not enough
experimental data about integration in the
whole-organism result;

= whole-organism result 1;

= whole-organism result 1 with cancer cells’ in­

tegration.

leading both tumor microenvironment with its internal cellular meta­ Considering the issue from this point of view brings us to alternative
bolism and whole-organism cells metabolism to such interaction that interpretation of well-known facts about oncogenesis. In case of ex­
would force cancer cells to co-organize their activity with the activity of perimental verification of previously stated propositions, we will get
the other cells again, forming another systems organization. basis for cancer treatment revision.

5
A.A. Venerin, et al.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ­
ence the work reported in this paper.
Acknowledgements
We are grateful to reviewers and editors for helpful constructive
comments and critical reading of this manuscript.
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