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INTRODUCTION
Glioblastoma
cells express on their surface CD29, CD44, CD73, CD90 and CD105 antigens, which
are also positive immunophenotypic signs for mesenchymal stem cells (MSCs)
[1,2]. It is also known that expression of CD90 on the surface of rat C6 glioma
cells is associated with identical Raman spectra in C6 glioma cell culture and
in MSCs culture [1,3]. Such identity or peculiar immunophenotypic signs in
undifferentiated cells can be explained. But in one case we are talking about
malignant undifferentiated cells (glioma and glioblastoma cells) [1,3]. In
another case, identical fingerprints are present on the membrane of non-tumor
MSCs [2,3]. So, in one case we are talking about undifferentiated stem cells
(SCs), a pool of which evolved in brain to increase efficiency of information
storage in neural networks. In addition, SCs are necessary for implementation
of reparative processes in brain injuries and diseases, that is, recovery of
normal brain activity. In another case, we are talking about malignant cells
(Cancer Stem Cells, CSCs) and their proliferation is associated with threat to
human life. By the way, scientifically based data on the ratio of body weight
at birth with the number of fetal SCs have been published [4].
Such associations in manifestation of
identical immunophenotypes of tumor and non-tumor cells raise questions in any
person who encounters the problem [5,6]. But after all, the same questions
“arise” in immunocompetent cells, which, when in contact with undifferentiated
cells, must decide on the correct behavior in each case. For example,
aggressive tactics of interaction with tumor cells following the decision of
immunocompetent cells ends with initiation of suspicious cells’ destruction
programs. And then the population of tumor cells is destroyed [7-9]. And what
if there was a mistake in “recognition” of suspicious cells and non-tumor
neuronal stem cells have been affected? In this case, destruction of endogenous
brain stem cells will weaken brain reparative potential. One can only assume
the implementation of such an erroneous mechanism, for example, in pathogenesis
of such diseases as Parkinson's disease, Alzheimer's disease, amyotrophic
lateral sclerosis and other neurodegenerative diseases.
The question on the interaction of SCs with
tumor cells remains unresolved, since there is in vivo evidence MSCs activity does not contribute to death, but to
proliferation of cells of malignant gliomas [10]. The authors [10,11] believe
that MSCs secrete exosomes, which form conditions in tumor cells for activation
of proliferative processes. Therefore, it is advisable to be wary of
publications about the effectiveness of MSCs against tumor cells. The result
depends on methodological features, for example, on the method of MSCs application
in vivo. If MSCs are injected into
bloodstream to treat brain injuries and receive signals from many of the body's
cells through which blood vessels pass, then, ultimately, a small number of
cells reach the intended site. Remaining MSCs scatter along the way to the
brain. It is difficult for MSCs to cross the blood-brain barrier. And finally,
MSCs enter the brain via unnatural way (with blood flow), and not by natural
ways of transmitting information to the brain, for example, through the cranial
nerves. MSCs from the blood stream enter the neuropil of brain and end up in
unusual conditions like Frank Sinatra's
Considering such fatal situations,
researchers are trying to use the tropism of SCs in relation to tumor cells and
place various antitumor substances and viruses into SCs in special migratory
containers [8,12]. For this purpose, combinations of human MSCs with
encapsulated antitumor drugs are used, which ensures active delivery of drugs
to the tumor and opens up new strategies in chemotherapy [12-14]. The prospects
of antitumor efficacy of MSCs loaded with human oncolytic viruses are analyzed
[15].
The emerging optimism regarding participation
and contribution of MSCs to antitumor processes in patient’s body has faded
significantly after becoming acquainted with the results of studies of an
international group of scientists [16]. The authors of this study evaluated the
effect of tumor-associated and normal MSCs in lung tissue on growth and spread
of primary tumor cells of human lung carcinoma. It was found that tumor
microenvironment (matrix) transforms expression of certain genes of MSCs, after
which MSCs are involved in the development of tumor metastasis [16].
Our team adheres to a somewhat paradoxical
hypothesis, which can be expressed concisely. In addition to undifferentiated
non-tumor stem cells (for example, mesenchymal, hematopoietic, neuronal, etc.),
from the very birth, tiny pools of undifferentiated tumor stem cells (CSCs) are
present in the human body. Why should a healthy body in the process of
evolution form a community of tissues and organs, including pools of SCs, MSCs
with CSCs? It turns out to be a kind of combination of incompatible contradictions
like in Friedrich Schiller’s “Intrigue and Love.” Let’s try to answer the
expediency of “incompatibility”. A small pool of CSCs in a healthy body is
needed to “train” immunocompetent cells to effectively prevent the migration of
CSCs to other parts of the body. At all stages of phylogenesis and ontogenesis,
a regularity is realized, which manifests itself in the fact that if the
relationship between cells and intercellular matrix is violated, for example,
when cells colonize the body’s spaces intended for other cells, conditions are
made for specific mutations leading to uncontrolled proliferation of tumor
cells including CSCs. Thus, the presence of miniature pools of CSCs allows
immunocompetent cells to taking a kind of training courses from the very birth
to prevent activation of malignancy processes.
The observation of life cycle of a naked
mole-rat (Heterocephalus glaber), in
population of which oncological diseases are extremely rare, is an aid to
development of such hypothesis [17]. Mole-rats are resistant to high levels of
carbon dioxide. Hypercapnia leads to increase of hydrogen ions concentration in
tissues and change of conditions familiar to tumor cells. It is known that
within tumor cells the pH ranges from 7.12 to 7.70 and in the intercellular
space of the tumor tissue it is 6.20-6.90 [18,19]. A shift in this ratio is the
reason for violation of optimal aerobic glycolysis conditions for the tumor.
CONCLUSION
A deeper understanding of mechanisms
governing the functioning of Heterocephalus
glaber’s systems will make it possible to advance in solving the fatal
problem of oncological pathology. To summarize the above, it is advisable to
emphasize the well-known truth about the attractiveness of scientific
discussions and disputes, and, on the other hand, the responsibility for
constant advancement in joint resolution of key issues of life and death.
ACKNOWLEDGEMENT
Our research project “Molecular markers and Raman
spectroscopy for evaluation of correlation between cellular heterogeneity in
tumor tissue and primary culture from the tumor tissue” was partially sponsored by Belarus-Lithuania
Fund: 2019-2020 (M19LITG-002).
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