Download Environmental Stress Factors

L.M.Zakaryan, H.S.Movsesyan, K.L.Manukyan /
Environmental Stress Factors and Molecular
Mechanisms of Cancerogenesis // Bulletin of the
International Academy of Science “Ecology and
Safety of Vital Functions”, #6 (42), 2001: 136-140
ENVIRONMENTAL STRESS FACTORS
AND MOLECULAR MECHANISMS OF CANCEROGENESIS.
L.M.Zakaryan, H.S. Movsesyan, K.L. Manukyan
NGO “Women for Green Way for Generations”, Armenia
Institute of Molecular Biology, Nat. Acad. of Sci., Armenia
According to the WHO data, because of malignant new formations more than 5 mln people die
yearly and by 2000 this number had reached about 8 mln. Mortality, caused by cancer,
obviously has tendency to increase. Of course, while studying mortality statistics, one should
be cautious: improvement of diagnostics may lead to seeming patient number increase: the
study of the past 60 years has shown that the population has more than doubled, life duration
has also increased. Yet, estimations have shown that cancer disease mortality is higher than
could have been explained by the above mentioned circumstances [4,9]. It is not soothing that
the disease gained the tendency to rejuvenation.
Currently, when oncological research is directed to studying both separate cancer cell and
organism regulatory systems on molecular and cell levels, it is clearly set that cases coming
down with cancer are increasing simply because the factors causing the said disease are
strengthening. We are living in a more dangerous environment, contaminated by mutagenes
and cancerogenes and we ourselves contribute to even more contamination through our
scientific- technical and industrial activities. Statistics research enables us to understand the
link between external environment and cancer occurrence (smoking and lung cancer,
irradiation and leucosis, sunburns and skin cancer and etc.).The year of 1915 can be considered
the beginning of experimental oncology when Japanese scientists succeeded in getting skin
cancer via rubbing coal-tar in a rabbit’s ear within 3 months [9]. Afterwards the active
component benzo(a)pyren was isolated from the coal-tar. Benzo(a)pyren is a substance of a
polycyclic aromatic hydrocarbon class and is being observed in many industrial mixtures up till
now [7].While discussing the issue of cancerogene effect of environmental chemical and
radiation factors, it is necessary to explain how hereditary information fixing tumor features in
generation changes.
Genotoxic factors and DNA - repair.
As it is known the preservation and the transfer of hereditary information in cell performs
DNA. Carriers of heredity- genes are set in DNA molecule in linear sequence. The totality of
all the genes is a program on the basis of which under certain environmental conditions the
whole complex of symptoms determining physical and mental essence of organism develops.
DNA possesses 2 main functions: 1) heterocatalytic- i.e. transfer of the information on protein
synthesis and about regulation of their enzymatic activity; 2) autocatalytic- i.e. function of
reduplication (DNA - replication).
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DNA is a highly organized chemical molecule. Together with cell it is subjected to the effect of
genotoxic factors, which are subdivided into
1) physical (ionizing radiation, UV- rays, electromagnetic waves, noises and etc.)
2) chemical (persistent organic and non-organic pollutants)
3) biological (some viruses, bacteria, fungi and genetically modified organisms).
According to the data of International agency on cancer research, viruses and heredity play a
subordinate role in cancer rate, about 80% of all cases of this illness origin is directly or
indirectly connected with physical-chemical pollutants of the environment [4,9]. The active
form of cancerogene interacts with DNA directly, bringing forth to single- and double-strand
breaks, modified bases, interstrand links and etc., which leads to the disturbance of DNA
matrix features, which are essential for its reduplication. The DNA damage type is
predetermined by the influencing factor. Mutagene, cancerogene and lethal changes take place
during the DNA replication on the matrix containing damages [1,3,6].
After the DNA structure decoding (in 1953) it took decades until the nature of striking stability
of genetic material became clear. It appeared that this phenomenon is stipulated not by DNA
metabolic inertness but by the existence of special systems, supporting and restoring genetic
structures integrity during the cell vital functions. The most important of them is the system of
DNA-repair mechanisms. Power and widespread of DNA- repair mechanisms on all the levels
of cell organization witness the biological meaning of their existence [1,6]. It is obvious that
the DNA damages are to be eliminated with maximum accuracy, since the basis of healthy
organism existence is its genetic stability and conservatism of the information. However, a
number of diseases are described when the DNA- repair and replication mechanisms are
disturbed. Most of them are characterized by high frequency of development of malignant new
formations, disturbances in immune status of the organism and others [1,6,7].
Is repair always successful? Regardless of how high the repair systems effectiveness and rate
are, we can’t confirm that every damage type is restored correctly, or that all the damages of
given type are thoroughly restored. The important cause to worry is non-repaired, falsely
repaired and non-repairable damages [1,4,7]. Tiny changes in molecular structure can cause
essential changes of biological features. Non-repaired and non-repairable damages are realized
as mutagenic and lethal. It is settled, that cell resistance to the damage factors effects is
provided by interaction of all the bifurcated repair systems; prereplicative, replicative and
postreplicative and so on. Only one potentially lethal damage is enough either to kill a cell or
to transform it into a cancer one. Depending on the character of the DNA damage and its
subsequent resynthesis, two repair types (“UV” and “”) are distinguished. The repair of
damages induced by chemical compounds goes either via “UV”- or “”- type, or through both
of them simultaneously - “mixed type” [1].
Despite prolonged latent periods in the tumor development process, there is a distinct “doseresponse” correlation. However, these correlations can’t bring to conclusion, that for chemical
cancerogenes and radiations exist threshold doses, below which they don’t influence. Some
DNA damages may be non-reversible regardless the dose [4].
Experimental studies, performed on animals, having got low-intensive radiation small doses
witness, that the mechanisms of cell and organism metabolism changes, are different in whole.
While high doses act the repair decreasing successfulness can’t be considered as a result of
insufficient repair capability, but is connected with great frequency of arising damages situated
very close to each other. Ability to repair and its effectiveness don’t decrease anyway, and the
cell is mobilized at most. In case of small constant or alternating doses repair effectiveness
decreases and the number of mistakes increases. However, radiation-induced cancer diseases,
arising as a result of non-repaired damages while getting small doses, don’t possess any
peculiarities which would enable us to differ them from the cancer, having been induced by
either radiation high doses or genotoxic chemical compounds. In other words for the genotoxic
factors no threshold doses exist [4].
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Apoptosis. An important response of the cell to DNA damages is the slowing–down or
stopping of motion through cell cycle. The inhibition degree depends on quantitative
characteristics of the damaging agent and on cell ability to restore the cycle motion rate [7, 8].
Recently, the issue of tumor growth specific gene-suppressor p53 participation in realizing the
cell cycle control and supporting cell genome stability has attracted much attention. The gene
p53 product is induced in response of various genotoxic influences able to lead to hereditary
changed pathological cells occurrence. In this case either p53–dependent block of cell cycle
takes place (which provides time for DNA-repair) with subsequent renewal of proliferation or
programmed cell death–apoptosis occurs [5, 7, 8].
Thus, on the one hand, DNA damages are considered substrate for repair enzymes, on the other
hand, they start the cell death program. Apoptosis is carried out through DNA degradation, to
which DNA- repair mechanisms hold out against [3]. These two processes compete not only
for cell substrate, but also for its energetics. In recent times new regulatory proteins, taking part
in the above-mentioned processes, have been revealed. Apoptosis is necessary for natural
innovation of organism tissues, and plays the role of hospital attendant, which removes
potentially malicious cells. In tumor cells apoptosis is remarkably blocked, which might be
connected with the suppression of activity of programmed cell death positive inductor - p53[7].
Currently 3 types of cell death are known: necrosis, apoptosis and final differentiation [2, 3, 5].
Necrosis (“nikros”-dead) is a cells toxic death. It occurs as a result of pathogenic factor direct
influence (microorganisms, physical-chemical factors), which disturbs the integrity of cell
membrane, that provokes inflammatory reaction in surrounding tissue. This, in its turn, leads to
immune cells migration to the damage center. The cell gradually falls apart as a result of
caryolysis, coagulation and protein denaturation, and instead of it connective tissue is formed.
Apoptosis (“apo”-separation, “ptosis”-fall) essentially differs from necrosis according to
morphological properties. Apoptosis initiation takes place in the result of expression of genesapoptosis inductors. Yet, cell membrane remains preserved. However, the synthesis of
proteases, which gradually begin to split the intracellular structures, increases. Cell wrinkles
and its volume reduces. Nucleus wrinkles during the final phases of the process. It witnesses
the preserved activity of a number of DNA sites. Dying cells undergo quick phagocytosis thus
not managing to get destructed. During this, inflammation doesn’t develop, the functioning of
neighboring cells doesn’t break and connective tissue replacement doesn’t take place, which
allows to preserve organ structure.
In the opinion of many authors, final differentiation is one of the apoptosis forms.
It is known, that some tissues are constantly renovated in normal conditions. They have cell
groups which are permanently divided actively and are in shortened cell cycle, and their
descendants stop being divided, function for special purpose for some time and then die. It
happens to blood cells: dividing cells are situated in bone marrow and ripe ones go out into
blood to perform specialized functions.
The biological meaning of apoptosis is to gradually get rid of cells, which at the given moment
are “unnecessary” from functional point of view as well as it consists in protecting mechanism
destroying the cells, which have become potentially dangerous caused by genome damage for
these or those reasons. By the balance of proliferation and apoptosis the necessary correlation
among the number of various cell types in tissues is provided. The suppression of the process
leads to hyperproliferative states, which are frequently considered precancer, moreover a
number of cells, having undergone the mutations, get the right to live. And the apoptosis
strengthening of separate cell types is lying in the basis of pathogenesis of a number of other
diseases (see the table)[3].
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Diseases connected with apoptosis strengthening or inhibition.
Apoptosis inhibition.
Tumor diseases:
Follicular lymphoma
Carcinomas with p53 gene mutation
Hormonally-dependent tumors
Breast cancer
Prostate cancer
Ovaries cancer
Autoimmune diseases:
System lupus
Glomerulonephritis
Viral infections caused by:
Herpes viruses
Adenoviridae
Possoviruses
Apoptosis strengthening
AIDS
Neurodegenerative diseases:
Alzheimer disease
Parkinson disease
Huntington chorea
Cerebellum degenerations, etc.
Aplastic anaemia
Liver toxic diseases
Niman-Pack disease
Up to now a number of compounds have already been revealed able to activate or block the
development of apoptosis, and in the genome of any cell there are areas, responding the action
of inductors and inhibitors of the programmed cell death.
Thus, the influences of stress factors of outer and inner environments of organism may lead to
mutation development and gene expression changes, regardless of the presence of powerful
protecting mechanisms.
Cell malignization and metastasing.
The genetic apparatus of the cell and organism on the whole, as mentioned above, is very
stable, but its quantitative overloading by evolutionary unexpected genotoxic irritants results in
a new quality. The second important matter is the inhibiting influence of cancerogenes on
immune system. This side of the issue is considered as extremely important, because between
the immunity insufficiency and cancer diseases growth there is a direct connection. As a result
of genetic disturbances the cell, and most possible the group of cells lose the ability to ripe and
are reproduced in an uncontrolled way without obeying the organism regulatory systems [4, 9].
The malignization first step is called initiation phase. The uncontrolled division feature of
tumor cell is transferred hereditarily. One transformed cell may cause the formation of “tumor
knot”. Today most of the researchers consider, that tumors have monoclonal origin, i.e. they
grow from one cell [9]. Malignant tumor differs from benign one by its ability to invase and
metastase. In the invasing process tumor cells grow into normal tissues, disturb their
functioning and nutrition, which eventually leads to the death of normal cells, to the shutting
off of the damaged organ functioning and then to organism death. Metastasing is the capacity
of malignant tumor to form tumor knots in those parts of the organism, which are far from the
initial tumor. Tumor cells, unlike normal ones, are very badly interconnected. Coming of the
main mass, single cells are spread throughout the whole organism via either blood or lymph
stream. In some organs these cells stay longer and start to get divided, in the result of which
new tumor knot is formed, which is able to invase. Even if tumor affects vitally unimportant
organ, the destroying of which doesn’t lead to organism’s death, its ability to metastase makes
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the tumor dangerous for organism’s life. Clinical physicians point out, that years later after a
successful operation on the patient, an analogical tumor may arise, often with other localization
(so called “late metastasis”). Cancer cells are able to remain in “sleeping” state in organism for
a number of years. In case of early diagnostics a full cure is provided on this stage. Not only
can migrating tumor cells be in “sleeping” state, but also sometimes transformed ones remain
as if frozen in the place where they have appeared.
Researchers currently pay most attention to oncogenes-DNA areas, responsible for birth of
cells with destroying features. Oncogenes are divided into viral and cellular ones and are
activated under the influence of chemical, physical and other factors. Therefore, it is logical to
suppose that if “sleeping” oncofactor exists in all the organisms, only certain conditions can
arouse this pathology [7].
Isn’t cancer a kind of revenge of nature?
Industrial chemicals, conservants added to food products, pesticides, some medical substances,
the increase of ionizing radiation and UV-rays radioactivity background, using in everyday life
radio and microwave appliances bring changes in cells genome, thus crippling heredity
conservatism. In the past only restricted professional groups contacted with cancerogene
substances: chimney-sweeps, workers dealing with aniline paint production, miners working in
copper and uranium mines, workers of asbestos factories. Yet, nowadays, cancerogene agents
are globally dangerous for the whole population. In big cities polycyclic hydrocarbons
(benzo(a)pyren and etc.) are observed in the air due to the smoke and exhaust gases of cars.
Therefore, it can be concluded, that they might be found in our food, too. Benzo(a)pyren was
found in vegetables, in cookery fats and vegetable oils, smoked products and so on. Pesticides
have been damaging not only insects. The widespread DDT can be listed in insecticide group,
having existing out of human control. Concentrated in food chain, DDT remains in fatty tissue
for a long-term period, and this is most dangerous. Asbest has become an important raw
material in contemporary technology and is supposed a serious pollutant in the form of asbest
dust, formed while brake washers are worn out.
A number of scientists consider, that during cancerogenesis quantitative factor obtains a certain
importance, since organism either on its own or with the help of chemical therapy can manage
only certain number of transformed cells [4, 9]. The lack of aetiological factor as an object of
therapeutical influence enables some specialists to consider, that the elaboration of treatment
methods of malignant new formations doesn’t have sufficient scientific reasons. Hence, the
legitimate conclusion is that the highest research priority belongs to preventive direction.
Therefore elaboration of new active methods of malignant new formations anticipations based
on already revealed pathogenetic mechanisms is so important.
The study of cancerogenesis molecular mechanisms and revealing the ways of influence on
their development are extremely important connected with directed transformation of
eucaryotic cell and with prophylaxis of mutagene influence of organism internal and external
environment factors. These matters are currently paid more attention, taking into account the
situation of radiation background persistent variability, of quantitative and qualitative
characteristics of mutagenes of chemical and biological nature in the environment.
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