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Proposed own view of the nature and etiological
classification of tumors. The article makes a number of conclusions. “Tumor
cells” do not exist in nature. The tumor develops due to the malignant dividing
normal cells. Carcinogens do not cause tumors, and are part of the mechanism of
tumor formation. The immune system is unable to distinguish cells of tumors of
malignant proliferation and congenital tumors from other normal cells of the
body. The immune system can play a key role in the tumor formation in case of
autoimmune diseases. But it can slow down or even eliminate the tumor process
caused by transgenic organisms. Tumors derived from transgenic microorganisms
can be contagious as other infections. Induced immunity makes a significant
contribution to the treatment of tumors. Disorder in the removal of the cells
production is a part of the mechanism of malignant proliferation. The mechanism
of malignant proliferation is not triggered by mutations in chromosomes in a
single cell or in the “tumor field”, but by the interrelated actions of all
cells and extracellular matrix substances involved in the process, and is
caused by an imbalance of stimulants and inhibitors of cell division and is
accompanied by a predominance of cell proliferation over apoptosis with the
modified architectonics of the cytoskeleton and the extracellular matrix.
Calcium initiates the formation of extracellular
matrix – a framework of self-structure. Tumor a hierarchical system of all
cells and tissues of the tumor and its metastases causing interference.
Keywords: Classification
of tumors, Malignant proliferation, Transgenic tumors, Gestational tumors
INTRODUCTION
Etiology and pathogenesis of the tumor diseases, in spite of the great
efforts in the study of their reasons and peculiarities, are in the range of
the most complicated issues of modern medicine. There suggested many theories
for the explanation of the tumors etiology [1].
a casual event
TUMOR CLASSIFICATION
A unified presentation of clinical and pathomorphologic data allows oncologists of different countries to describe and evaluate similar tumors in a similar way. The international classification of oncological diseases (IDC-O-2) published by the WHO in 1990 is a fundamental document in this area [2]. The tumor-related
In my opinion, tumors are divided into four
types: tumors of malignant proliferation, transgenic tumors, gestational tumors
and tumors genetic aberrations.
The tumors of
malignant proliferation
Malignant proliferation is a process in which
normal cells have to divide continuously as a result of two factors at work in
the same time – continuous division stimulation and absence of division
inhibition. In this category, we have hormone-dependent tumors caused by
failures in the feedback between stimulating organs and target tissues.
According to the popular gene mutation theory
of tumor etiology, it is gene mutations that take place when the cell is
exposed to carcinogenic factors that cause oncological diseases [3-5]. These
mutations transform normal cells into “tumor cells” with rapid uncontrolled
proliferation. This hypothesis is hardly correct as tumors quite often regress
[6-10] and the nucleus of a tumor cell when transplanted into a normal
enucleated oocyte would behave normally [11]. Encyclopedic information: “a
mutation is the permanent alteration of the cell properties or an organism,
which can be inherited by the descendants of the given cell or the organism”
[12]. The extracellular theory [13] holds that the behavior of cells (division,
stable functioning, aging and death) are determined not by gene mutations but
changes in the tissue structure – composition of the cellular membrane,
extracellular materials, tissue stroma induced changes, cell sensing systems
(CSS) similar to quorum sensing systems (QSS) of microorganisms.
In my view, tumors of malignant proliferation
start growing when normal cell proliferation is stimulated while the inhibition
of the process is impaired either as a result of changes in the inhibitors or
the loss of the ability of the cells to interact with them. Both mechanisms are
a result of changes in the composition and structure of cells and tissues with
subsequent changes in the functions of the cells and extracellular matrix.
These changes can be caused by certain interrelated factors such as slower
clearance of substances from tissues, slower autophagia, accumulation of
carcinogens that can interact with extracellular matrix and form insoluble
compounds. A mismatch of cellular division stimulation and inhibition leads to
uncontrolled proliferation of normal cells.
In my opinion, the reason of the tumors of
the malignant proliferation is the stimulation of the division under functionality
of the inhibitors of the division, which can be a result of the production of
the distorted inhibitors, and also because of the inability of the cell to come
into contact with the inhibitors. Both mechanisms are stipulated by the changes
of the composition and the structure of the cells and tissue that entails the
changes of the cells and extracellular matrix functions. These changes arise
under the influence of a number of the interconnected factors: the decelerated
removal of the substances from the tissues, the autophagy deceleration,
accumulation of the carcinogens, which provide the insoluble compounds with the
extracellular matrix structures. In the situation when the cells have the
stimuli for the division and the effect of the inhibitors’ influence is slowed
down, the unrestrained proliferation of the normal cells comes. There is the
evidence the extracellular matrix may initiate carcinogenesis [14] through the
infiltration of altered tissue by means of monocytes. Together with them,
T-lymphocytes migrate and accumulate, and then an extracellular matrix
including I and III type collagen, proteoglycans, elastin is formed. The flow
of calcium into the intercellular space is associated with the formation of
soluble complexes of calcium ions plus amino acids, glycosaminoglycans of the
basic substance, collagen and elastic fibers of connective tissue. Calcium ions
are integral components of many biostructures and evolutionarily ancient
mediators, and they regulate many metabolic processes and physiological
functions. It is calcium that initiates the formation of the extracellular matrix,
i.e., the basis of an independent structure. If cells have stimuli for division
and the action of its inhibitors is blocked, uncontrolled proliferation of
initially normal cells occurs.
Substances that stimulate cell division are
synthesized by the cells and act within the cells [4]. Those found in the cell
microenvironment interact with the cell surface [15,16]. The proliferation of
different cell types is determined by a totality of growth factors rather than
just one of them. A big group of growth factors is represented by cytokines
(interleukins, tumor necrosis factors (TNF), colony-stimulating factors (CSF)
and others). All cytokines are polyfunctional; they can both enhance and
inhibit proliferative reactions. In normal eukaryotic cells, the cellular cycle
is regulated by alternating activation/inhibition of different complexes of
cyclin-cyclin dependent kinases (CDK). Incorrect expression of any of these
cyclins leads to genetic instability. The CDK activity is determined by several
mechanisms. Additionally, some cyclin-CDK complexes can be blocked. The binding
of a growth factor to its receptor on the cell surface triggers the activation
of certain pathways and further to the activation of some cyclin complexes
which trigger the transcription and expression of the proliferative response
genes that induce DNA replication and cell mitosis. Mature undifferentiated
stem cells support tissue regeneration when they proliferate being exposed to
certain stimuli. The knowledge of the mechanism determining when, where and why
stem cells start to regenerate or differentiate is limited though their
microenvoronment was shown to produce necessary signals shaping further
behavior of these cells [17,18].
The accumulation of cellular metabolites has
a detrimental effect on cell components and functions, induces changes in
tissue homeostasis and ultimately produces a critical damage of the whole
organism. There are different medical conditions associated with enhanced
accumulation of cellular metabolites such as lipids (lipidosis, steatosis),
cholesterol and its esters, proteins, glycogen, pigments (chromoproteins,
lipofuscin and melanin), bilirubin, calcium, hyaline and so on.
Water-electrolyte imbalance with fluid retention is yet another important
factor. The accumulation of cellular metabolites leads to cell enlargement and
aggregation, and reduction of the intercellular space. Under these conditions,
the cell cycle becomes unstable, autophagia is reduced, the production of the
target of rapamycin (TOR) is increased while that of sestrins is reduced. All
this impairs cell recovery and antioxidant mechanisms. The oxidative stress
caused by lipid peroxidation, oxidation of proteins and oxidative modification
of the genome, mitochondria and DNA plays an important role in oncogenesis.
Autophagia helps cells get rid of damaged mitochondria and replace them with
new ones. Aging mitochondria produce high levels of active oxygen species or
free radicals that destroy tissues. Autophagia is reduced with aging, which
enhances the accumulation of damaged proteins prone to aggregation.
Sestrins produced by stressed cells activate
AMP-activated protein kinase (AMPK) and inhibit target of rapamycin (TOR). AMPK
and TOR are two protein kinases that are very important regulators of metabolism
and aging. When the release of metabolites from the cells is restricted, TOR
production is increased while that of sestrins is reduced. AMPK is activated in
response to a reduction in energy utilization (a factor slowing down the aging
process) while TOR is activated in response to excessive energy level at which
aging is faster. AMPK activation inhibits TOR, and drugs that activate AMPK and
inhibit TOR can slow down the aging process. Accumulation of aging cells
associated with a reduction in the number of stem cells diminishes the
proliferative potential of regenerating tissues, stimulates cell division and
initiates tumor growth. Tumor growth is constrained by normal healthy cells.
The processes are slow while proliferative cells are still in contact with
tissue matrix and normal cells. When cellular receptors of the cell division
inhibitors are blocked but the cell is stimulated for division it acquires new
characteristics and enters into a state of spontaneous division. This is
manifest as a rapid tumor growth (expression).
TRANSGENIC TUMORS
Transgenic tumors are a result of
incorporation of some viral or bacterial genetic material into the genetic
apparatus of the cell. This gives rise to a foreign microorganism the behavior
of which is determined by its own capabilities and its environment. The fate of
this hybrid is determined by the immune and hormonal systems of the macro organism
and the biopolicy of other microorganisms.
As was shown in the 50s of the last century,
viruses can become incorporated into DNA cells and replicate with them. Modern
genetics has established the existence of horizontal gene transfer, which
allows assuming that a combination of the genetic material of microorganisms
with the cells of the macro organism is quite possible. The cell genome
receives new information that distorts its life cycle and changes its biology
[19-22]. The data presented in the review are convincing but their
interpretation can be different. As is generally accepted, viruses and microbes
change the cell genetic apparatus and transform a normal cell into a tumor cell
that will be similar to cells of other tumors. I believe that this
hybridization results in the appearance of a separate entity, a new
microorganism with new features and obeying its own laws. Colonies of such cells are actually tumors
that differ from other tumors by their origin and structure. The behavior of
the hybrid microorganism is determined by the immune system of the host, its
interaction with other microorganisms, by the extracellular matrix, surrounding
cells and division activators. They do not have division inhibitors. It should
be noted that some carcinogens destroy the extracellular tissue structure and
thus change the normal proliferation process, contributing to a faster penetration
of the virus into the cell and formation of a hybrid.
Gestational tumors include tumors of dysembryogenesis, as well as germ cell tumors,
trophoblastic and coelomic epithelium tumors.
The nature of induction influences as well as
causes and mechanisms of cell migration are not yet fully understood. It is
still unclear what changes the migration of sex cells. We still do not know the
mechanisms underlying the division of the internal cellular mass (the
embryoblast) and why they become faulty. I believe that faulty embryogenesis
with migration of sex cells and division of the internal cellular mass is a
cause of these tumors.
TUMORS OF GENETIC
ABERRATIONS
Scientists know several hundreds of
hereditary biochemical defects in the human body, caused by changes in the
genetic constitution of the individual [23,24]. The hereditary aberrations of
the p53 gene are associated with the
violation of DNA repair, which cause breast cancer, sarcomas, leukemias, CNS
tumors, adrenal tumors, epithelial tumors. Some chromosomal rearrangements play
a leading role in developing congenital and hereditary human oncological
diseases.
DISCUSSION MATERIAL
Numerous publications in this area show that
there is no clear understanding of what happens in oncological diseases. No hypothesis
can explain spontaneous malignization in
vitro. None of the existing hypotheses is universal and covers all
mechanisms of carcinogenesis. Ideas generalizing available findings are yet to
be postulated. The concept that all tumor types have the same cause has never
been validated and the treatment of cancer is still a serious medical issue.
Oncological diseases are believed to be
caused by carcinogenic factors [25-28]. The very word carcinogen means a source,
inductor, trigger of tumor. They are but a component of some carcinogenic
mechanism rather than the primary cause of cancer. Moreover, tumors can grow
even in the absence carcinogenic factors. Carcinogenesis can be stimulated by
certain hormones and vitamins that activate cell division accelerate metabolism
and increase the production of cell metabolites which tend to accumulate in the
tissues. While the negative role carcinogens play in dysembryogenic tumors is
not yet established, in tumors of malignant proliferation they damage the
architectonics of cells and extracellular matrix, impair the clearance of
cellular metabolites, cause a reduction of the intercellular space and increase
cell aggregation. In transgenic tumors, they facilitate the penetration of
viruses into the cells.
My remarks on carcinogenesis should be
regarded as a stimulus to the search of other explanations of carcinogenesis
rather than criticism of the role carcinogens are believed to play in this
process. The oncological concepts presented here are based on the extracellular
theory [13], which holds that the life and
behavior of the cell is completely determined by extracellular materials in its
microenvironment. My concept is well in line with the tissue theory of cancer
proposed by Cherezov [29], though I do not believe that there is a common
denominator for all carcinogens and all cancers as their etiology is different.
Aging is but a part of the carcinogenic
mechanism in the organism. The latter also includes autoimmune processes and
exposure to surfactants. The mechanisms of aging, cell cycle and DNA repair are
intensively studied in different countries as oncological diseases are
associated with impaired mechanisms of cell proliferation. Aging is mainly
related to the aging of collagen and extracellular matrix dysfunction causing
aging of cells which lose their ability to self-regeneration and reproduction,
to store hereditary information and restore it in case of failures [17,18]. The
growth of tumors is determined by numerous factors at work not within
individual cells or limited “tumor field” but in the whole tissue or body.
Tumors can start growing either consecutively or synchronously in different
tissues. Tumors appear at sites where the impact of negative factors is the
strongest. Widely used domestic surfactants as a factor of carcinogenesis are
underestimated. Even in minimal (trace) amounts, surfactants absorbed with food
change intercellular interactions and adhesion.
Petrov [30] pointed out that tumor cells do
not have a universal morphological feature that will distinguish them from
normal cells. As we know, tumor cells are not characterized by some specific
protein, enzyme or fermentation reaction that cannot be found in normal cells
at some stage of ontogenesis. Human tumors are shown to contain no antigens that
cannot be found during the normal embryonic development of tissues. There is no
genetic defect such as loss or appearance of a new product encoded by some gene
that will be common for all malignant tumors. Malignancy of cancer cells is not
inherited as daughter cells can normalize. Thus fibronectin added to cultured
cancer cells of malignant proliferation significantly improves adhesion
[31-33]. The addition of fibronectin restores the normal highly ordered
distribution of a major cytoskeleton component – the network of filaments made
of protein actin. These facts plus a gradual growth of tumors from initial
precancer lesions run counter the concept of mutational changes causing cancer
and indicate that the course of events leading to cancer is different.
Nevertheless, a cell of malignant proliferation cannot be called normal as its
“young’ features become manifest not in the right place and at the right time.
Such an aberrant behavior can be a result of either deficit or excess of
substances normal cells are composed of.
Compromised immunity is believed to be
closely associated with cancer [34-36]. When the immune system functions
normally it can rapidly eliminate appearing cancer cell. The role of the immune
system in the control of transgenic tumors, like of other infections, is indeed
critical but the immune system cannot cope with tumors of malignant
proliferation and dysembryogenic tumors as it cannot differentiate their cells
from normal ones, irrespective of its status. The immunity status determines
the autoimmune response. Thus systemic autoimmune diseases of the connective
tissue have an impact on different organs and are manifest as fibrinoid
necrosis. Autoantibodies that are formed in this process interact with the DNA
and other cellular components such as cytoplasm and cytoskeleton (and its
actin), as well as with matrix collagen [37-39]. Structural changes in DNA lead to
functional changes and then to the death of cells, which stimulates the
division of other cells. Malignant proliferation is not possible if the
cytoskeleton is intact. It can be stimulated when division inhibitors are
blocked as a result of damage of collagen in the extracellular matrix. Collagen
damage of the extracellular matrix leads to blockage of the division
inhibitors, which also contributes to malignant proliferation.
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