Mitochondria and cancer

A new understanding of the formation of tumors

I propose to look at the problem of tumor formation from the position of a single membrane-mitochondrial complex.

Cell membranes are complex sensory mechanisms that automatically control the external conditions in which the cell lives, and correct the work of cells according to changing conditions. These sensory mechanisms determine the functioning of the mitochondria and the nucleus. Violations in them lead to a failure in the functioning of the nucleus and its genome. Thus, the problem of the formation of cancer tumors is seen to us as a violation of the relationship between mitochondria and cell membranes, and not as a simple mutation of mitochondria. Without the presence of previous long-term damage to the cell membranes of the cytoplasm and mitochondrial membranes can not explain the initial stages of tumor formation.

Tumor growth begins not from one cell (as it is supposed in the theory of mutation), but from a certain part of tissue. Consequently, degenerations in membranes and the inferiority of antioxidant systems are primary, and in the DNA of mitochondria the consequences are secondary. The cycle of cell development becomes truncated, only primitive ancient gene programs work. All this confuses researchers and makes them look for the cause of disorders at the genetic level-in the genome of the cell nucleus. And there really “find” such oncogenes, for example, p53, etc. They are described, understood, but are a reflection, a secondary adjustment result in sustainable changes in mitochondria-targeted antioxidants, membrane level. Mitochondria have their own DNA, but their purpose is to regulate the energy process in the Krebs cycle. The mitochondrial DNA is significantly different from the DNA in the nucleus.

Membranes are the “Achilles’ heel ” of cells, primarily damaged by various factors. The possibilities of self-defense and recovery in such cells are much limited. They are the basis on which the process of malignancy (degeneration of healthy cells into cancer, malignant) can develop.

The proposed dual mitochondrial-membrane approach to the solution of theoretical and practical problems of Oncology allows us to link many disparate results into a single whole. For the first time it became possible to substantiate and solve practical problems of treatment with the maximum possible effect with complete harmlessness of the method.

In the light of the proposed theory, it becomes clear why the solution to the problem of Oncology only by restoring the energy of cells and their mitochondria is impossible. The fact is that even in the case of achieving a positive result for the resorption of the tumor and the disappearance of metastases, there is a great threat of recurrence of the disease in the period from one to 5 years. Large tumors do not respond well to treatment, and need to connect to other mechanisms, including increasing immunization and immunogenicity.

Unfortunately, the doctors still do not recognize these treatments as a main or as a subsidiary.

The role of mitochondria in tumor formation

Previously, the membrane-mitochondrial approach to the explanation of carcinogenesis has already been put forward by a number of authors. Below I will give their theories. They have great advantages in solving the problem of treatment of tumors in comparison with previous theories, but also a number of drawbacks, since they can not explain many aspects of the primary processes of malignancy — the degeneration of ordinary cells into malignant. Part of this process, the researchers missed.

Energy concept of the oncological process of O. Warburg (1927).

He found that malignant tissue degeneration is accompanied by a significant increase in aerobic and anaerobic glycolysis (the process of obtaining energy in the presence or absence of oxygen). Breathing using oxygen in cancer cells is replaced by another type of energy — glucose fermentation, characteristic of lower forms of life.

According to his concept, the cause of malignancy is respiratory failure and compensatory increase of glycolysis in those cells that survive after respiratory injury. The ability to obtain energy through “lactic acid fermentation” glycolysis and grow through the energy of this process is the main biochemical characteristic of tumor cells. Warburg concluded that cancer cells were different from healthy cells, including growing embryonic cells, by being unable to suppress glycolysis in the presence of oxygen.

Realizing that the energy of the cell is associated with mitochondria, the scientist first suggested possible violations in the mitochondria. But this statement was left without attention for a long time.

Membrane theory of cancer Natacha S. A. (1961)

From his position, the peculiarity of the energy of cancer cells is determined by a defect of mitochondrial membranes and an increase in the synthesis and catalytic power of hexokinase, which limits the rate of glycolysis in cells. Membranes determine the work of enzymes. While correctly interpreting some of the enzymatic aspects of the cancer process, Neifach could not explain the stability of this process in subsequent generations of cells and much more.

Inozemna hypothesis Shapot V. S. (1968, 1975)

The biochemical features of the tumor do not depend on the appearance of new enzymes in the cells, but on the disorder of the sequence of synthesis of isoenzymes (or isoenzymes — different forms of the same enzyme, existing in one organism, but, as a rule, in different cells, tissues or organs), which are present in normal cells. As a result, the ratio of some of the enzymes changes, which leads to an increase in the rate of glycolysis and a change in its interaction with other metabolic processes. It is shown that the difference in the isoenzyme composition of normal and tumor cells relates to enzymes such as hexokinase, aldolase, pyruvate kinase, lactate dehydrogenase, adenylate kinase, etc.But this only partially explains the formation of the tumor, being only part of the mechanism of carcinogenesis.

Mitochondrial theory of Zotin cancer (1991).

Only in the last decade received a lot of data on violations in cancer cells of the structure and function of mitochondria — organelles, performing the function of breathing. This allowed us to propose a mitochondrial theory of cancer, which to some extent complements the approach of Warburg. The concept proceeds from the previously put forward idea that the occurrence of malignant tumors is associated with the appearance of mutant, defective mitochondria in cells.

As the author notes, the case is not in complete violation of cell respiration, but only in violation of the reproduction and structure of mitochondria, damage to their outer membrane, increasing the permeability of the latter and, as a consequence, changing the regulatory mechanisms of respiration and glycolysis. As you can see, attention is paid only to the outer side of the mitochondrial membranes and there is no interconnection with the cell membranes as a whole. Namely, this membrane may define many internal processes, such as mitochondria and nucleus of cells.

In order to create his theory, Zotin needed to explain: how changes in mitochondria, leading to the emergence of energy metabolism of cancer type, associated with the activation of oncogenes of transformed cells. In other words, what is the connection between the theory of Warburg and the theory of oncogenes. According to the author, “in the mitochondrial theory there is still a lot of uncertainty, both in detail and in General.”

And most importantly – this theory describes only part of the more global rearrangements in the cell. Many scientific facts are not linked in this concept. For example, the fight of immunity with culling them, which is proven. This explanation is possible only in view of the fact of degeneration of the outer membranes of cancer cells. Also, this theory does not take into account the Pro-inflammatory initial side of carcinogenesis, which in turn can also be associated with the outer membranes of cells.

Therefore, this theory is only a narrow view of the mechanisms of cancer at the cellular level and is not able to bring together all the disparate facts. At the same time, this concept can only explain the already manifested cancer process, but not the primary stages of cancer, which are more likely to be determined by the outer membranes of cells, while intracellular rearrangements can be secondary adjustments, overstrain energy processes in certain groups of cells, followed by the process of looping.

Regulation of energy processes

It is in the mitochondria are genetic programs that are responsible for the most perfect mechanism of energy, ie Krebs cycle. They determine whether this cycle will be a full-fledged aerobic PLI everything will go on the anaerobic (oxygen-free) path.

Certain mitochondrial genes may be turned off or on depending on changes in the elemental composition of the substrate. Mitochondria work always, even when the body is starving, because the respiratory and energy processes and heat are continuous. Genes determine the activity of Krebs cycle enzymes. It is known that many genes in the genome are sometimes duplicated hundreds of times. Such excesses are confusing.

There is reason to believe that each gene product is regulated in mitochondria not by one gene and not only by subsequent transcription of RNA on ribosomes with multiple reading and formation of copies of proteins and enzymes, but also by a whole block of genes-duplicates that are parallelized in the battery. The activity of the genes responsible for energy is obviously regulated in some other way. But what is clear is that they react to the state of their environment. It is known that mitochondria can exist autonomously and outside cells, while cloning themselves. So they have a set of self-Assembly genes, DNA, responsible not only for energy processes. The peculiarity of DNA regulation in the field of energy allows the system to be controlled not just by on-off, but more subtly respond to different levels of the environment.

In addition, this feature of the DNA mitochondria explains the greater likelihood of damage. At the same time, it becomes possible, if necessary, to correct the work of genes.

This connects more or less enzymes responsible for a certain link in the Krebs chain. Energy products in the course of mitochondria is formed many times more than in conventional construction processes in the cell. And for these purposes, special organelles are needed, the connection of the program is possible only when a certain threshold is overcome. Such a complex genetic program acts as a sensitivity sensor, a relay network reacting to the concentration threshold. In this situation, not all genes responsible for this process are usually violated in mitochondria, but only a part of them.

The question is: is it possible to achieve their reparation from such working mitochondria?

In principle, it is possible to bring cancer cells to the level of healthy cells by increasing their energy. This is confirmed by the data on the use of copper and succinic acid.

It is known that stable glycolysis, except onkokletok may show and embryonic cells. Differential genes have them, too, blocked.

It should be understood that mitochondria in cells can be many, from five to hundreds. Their number obviously depends on the energy needs of the cell. Failure of one mitochondria should not affect the General condition of the cell. Normally, if the work of many mitochondria is disrupted, the mechanisms of apoptosis — self-destruction are triggered. But this is not happening. Why?

The energy processes in the not occur primarily in mitochondria and in the cytoplasm of cells. That perfect Krebs cycle with a flexibly controlled chain of enzyme links, which is available in the mitochondria, is not here. By the way, here is the “Achilles heel” — a weak point of the tumor.

In such aberrant cells, due to violations of the sensitivity threshold, there is a perverted reaction of the inclusion of programs to repair, reproduction, which is associated with mechanisms of inflammation at the cellular level. Inflammation increases repair. Obviously, this can explain a certain relationship inhibition of the growth of cancer cells, for example, anti-inflammatory drugs such as aspirin.

Now it becomes clear why the proposed antioxidants and oxygenators have a certain effect in the treatment of cancer, in particular, selectively promote apoptosis (natural cell death) of cancer cells without affecting healthy cells, weaken onchangeevent (sprouting of vessels in the tumor) and metastatic development.

Studying, for example, the mechanism of action of cyanidin-3-rutinoside (C-3-R) obtained from BlackBerry on malignant cells, the researchers found that this substance leads to the accumulation of active oxygen compounds in the mitochondria of cells, which in turn triggers the process of programmed cell death — apoptosis. Mainly this effect is given by antioxidants of the polyphenolic group contained in black berries, for example, black grapes, Irga, elderberry, betaine coloring substance from beets and others. But other groups of antioxidants, including mineral ones, such as selenium, fat-soluble ones, such as lycopene, vitamin A and others, also have a certain value.

Reversibility of cancer cells

My proposed theory takes into account the facts confirming the ability of tumor cells to normalize during differentiation.

Impressive results were obtained in studies on moralistically opportunities teratocarcinoma cells [2] mouse (Mintz, 1978). Scientists have demonstrated that cancer cells teratocarcinoma capable of a complete loss of signs of malignancy and inclusion in histogenesis — the restoration of healthy tissues [3] . The cells of non — embryonic tumors, such as breast adenocarcinoma, squamous cell carcinoma, chondrosarcoma, had the same properties (Pierce, Speers, 1988).

The degree of malignancy of the tumor, it became possible to explain not a violation of specific groups of genes, and depth of impaired glycolytic process — the amount of damage to the mitochondrial genome of telephone It means that the energy function of a certain generalstate unit may be switched off, not fully, but only partially, and restricts in varying degrees the energy.

On the expediency of combining the theories of carcinogenesis

Previous theories had contradictions that could not be put into a single system. For example, information that cells with chromosomal abnormalities in differentiation are normalized, losing malignancy (Saks, 1986).

Autonomy easily explained from the standpoint of their aberrant inferiority. It became possible to interpret this aberrance as a result of power plant failure. It is known that all cells can exist without mitochondria. Mitochondria-the later acquisition of evolution. It is believed that this was due to the merger, the symbiosis of the simplest eukaryotic cells with certain Autonomous structures. This symbiosis allowed cells to move to new stages of evolution. The mitochondria in your cells is a relatively independent structure with its genetic apparatus.

Repair (recovery) in cells with cancer is still possible, but for this it is already necessary to create certain conditions in which the metabolism (metabolism) of cells will proceed, so that blocked programs of the mitochondrial genome are connected.

Some authors argue that the growth factor for cancer cells can be isolated from the cystic form of worms or fungi that live in the blood. All this a huge number of factors can contribute to the manifestation of the disease, but without intracellular predisposition they are not able to start it on their own.

These authors try to present the General picture in such a way: in the increased mode of proliferation, the violation of the structure of tissue homeostasis determines the shift towards embryonalization, which changes the ratio between stimulators and inhibitors of mitosis (cell division), as a result there is “overstimulation”, and the tumor grows. Thus, the tissue model binds carcinogenic profile, proliferation regime, the degree of rejuvenation, distortion of the structure and function of homeostasis, uncontrolled growth of clonogenic cells.

According to the theory of oncogenes, in normal cells there are inactive proto-oncogenes, which in the process of transformation are pathologically activated, eventually provoking the formation of a tumor. But this activation should be explained by a secondary reaction to a violation of the energy homeostasis of the cell.

Recent data show that malignized (malignant) stem and commited cells, as they do not need genetic changes, because they already have a set of “malignant” properties. Therefore, in cancer cells can move actively mitrousi (dividing) cells. In them of possible power failures.

Embrionalnuju cancer cells can be explained by the shutdown of programs of mitochondria. Embryonic cells can also exist in oxygen-free energy, i.e. without mitochondria.

It can be assumed that cancer cells do not come from any, but from stem, clonogenic cells. And the peculiarity is that in them there is a violation of intracellular energy homeostasis due to degeneration of mitochondria and membranes. Oncology is obviously the imposition of aberrant processes on clonogenic cells.

A similar increase in resistance to apoptosis occurs in aging cells. Reducing the rate of culling of old and sick cells – “costs” of old age. Thus, the absence of apoptosis is not a purely oncological problem, but a secondary universal process associated with the level of aerobic respiratory energy processes. Where there is a decrease in mitochondrial activity, there is weakened and apoptosis, regardless of mitotic activity. Therefore, apoptosis — function, adjustable strong aerobicise process. Old cell lines, unable to die, block the way to the growth of stem cells. As a result, the ratio of old cells to newly formed young cells is in favor of the former. Aging occurs at the cellular level of the entire tissue, and then the body as a whole. The task of geriatrics is to accelerate the culling of old cells and increase the activity of the growth of young clonal cells.

Imposing aberrant (genetic disorders) processes on clonogeneic cells can obviously lead mainly to degenerative processes, i.e., by their mere degeneration. This is the Foundation for all sorts of atrophic and involutional processes, slowing metabolism with age and, of course, for aging tissues, and the whole body as a whole.

Experiments on transplantation of tumor cell nuclei into pre-enucleated (artificially deprived of nuclei) embryonic cells are well known, when the nucleus (genome) of cancer cells is inserted into the cell deprived of its own nucleus. In this case, a healthy body develops, and not affected by cancer, which once again suggests that the mechanisms of cancer lie outside the cell nucleus.

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