“Journal of Medical Science Academy of Ukraine”, 2004, v.10, №1. – p.50-64 UDC 616-006.04:612.017.1 (Recommended by Corresponding Member of MSA, Ukraine V.A.Mikhnyov)

Specific immune reaction of organism as initiator and promoter of carcinogenesis

Oleksandr V. Shevchenko, Vol. O. Shevchenko, V.O.Shevchenko

Having considered the published data, but devoid of rational explanation in due time, the authors put forward a hypothesis about the decisive role of an organism’s specific immune reaction in pathogenesis of malignant tumor process. The hypothesis was shown not to contradict a contemporary vision of the mechanism of malignant tumor development. It was concluded that the induction in tumor- hosts of immune tolerance to tumor antigens makes retransformation of tumor cells to normal ones possible.

Key words: tumors, immune reaction

One of the principal tasks of a theoretical study in any field of knowledge consists in determining that standpoint, from which the object of research could be revealed in the simplest way possible.

D.Gibbs

The problem of immunologic interrelations between malignant tumors and host is very complicated and intricate. More than a hundred years have passed since the experiment showed the possibility for cancer immune prevention, but the creation of highly efficacious immunologic modes to treat malignant tumors is still waiting for its time to come.

When starting to present our vision on one of the immunological approaches to solving the problem of malignant tumor growth we find it necessary to submit a concise description of its general picture while dwelling at some greater length on those chapters only which are directly associated with the idea asserted in this publication.

As back as the early 20th century S. Jensen published his work wherein he, being based upon the results obtained in the performed research, stated the idea concerning the possibility to artificially create an active immunity to malignant tumors [29]. Soon after, P.Erlich with his colleagues joined in studying this problem [40]. In the fashion analogous to the methods, applied in bacteriology, they immunized animals with avirulent tumor material, developing their resistance to inoculation of already virulent tumors. However, the interest to the research in this area decreased and up to the middle of the last century only isolated reports appeared about the works dedicated to studies of the immunity to tumors. It’s not until the works by E.Foley [28], R.Prehn and J.Main [37], R.Beldwin [21] and others had been published that the researches in the field of tumor immunology were dramatically activated. Using auto- and syngeneic systems, researchers clearly identified the presence of the phenomenon of antitumor immunity. The animals, previously injected with inactivated malignant tumor cells, gained resistance to inoculations with the living tumor material. Almost all the elements (humoral as well as cellular ones) of the immune system were found, and not only in experiments but also in clinic, to be involved in the formation of antitumor immune reaction. However this mechanism doesn’t ensure any protection against malignant tumor growth in natural conditions. This is associated with a number of circumstances. As it has become clear, along with the evolvement of immune reactions having an antitumor trend, their blocking mechanisms come into action. Apart from this, there’s one more phenomenon making the situation much more complicated – it is immunostimulation of tumor growth (this phenomenon will be regarded in detail further on). Such interweaving of the processes, having different trends, is apparently responsible for the current state of the immunotherapy, when it is capable of performing, and not always though, a secondary role only. To make sure that it is really so, one can open the last edition of the capital manual on the treatment of malignant tumors “Cancer Medicine” [20]. The following is said there about the possibilities of the immunotherapy: “…favorable results of the immunotherapy can be observed only in patients having microscopic manifestations of the disease provided that the adjuvants were applied after all the clinical tumor manifestations had been eradicated by means of traditional treatment methods”.

Nowadays titanic efforts are being made to boost an organism’s immune reaction to the efficient level by means of antitumor vaccines. A great number of research institutions and firms are engaged in creating them. [19, 26, 27, 31, 32, 41]. However, not all assess unambiguously the prospects of this direction. So, R. Prehn, a lead theorist in the area of antitumor immunity problems, for example, treats it with caution, admitting though the perspective of antitumor vaccination with embryonic tissues [34].

When analyzing pathogenesis of malignant tumors, we paid attention to the phenomenon of malignant transformation of embryonic cells transplanted into ectopic (extrauterine) sites of adult syngeneic animals. This phenomenon has not received any unified theoretical interpretation as yet.

Its exceptionality consists in the fact that embryonic grafts undergo malignant transformation without any carcinogenic impacts, i.e. there takes place carcinogenesis without carcinogens. This fact became the basis for shaping our views as to the role of an organism's immune reaction in carcinogenesis which differed from those generally accepted.

In the late 70-ies and early 80-ies of the 19th century J.Cohnheim’s views concerning the origin of malignant neoplasms were shaped [25]. According to J.Cohnheim malignant tumors can be developed either from the remaining embryonic tissues that happened to be among the definitive tissues of the same histogenesis but, due to some reasons, were not involved in the normal tissue building process, or from the embryonic residues, transferred to another site, which appear to become a heterotopic object and therefore are not involved into intratissular interrelations. These embryonic residues give rise to neoplastic growth. In order to prove or disprove this hypothesis the embryonic material (tissues or embryos’ parts) was transplanted into adult animals however there was no growth of tumors from them. But when embryonic cells, isolated from the embryos in pre-implantation period, were implanted into the extrauterine sites of adult syngeneic animals, they were naturally transformed into malignant ones. A well-known expert on the problem of malignant cells’ differentiation, I.Shvemberger spoke on the subject as follows: “The fact that no tumors develop in the case of the ectopic transplantation of definitive tissues allows the ectopic grafts’ malignant transformation from embryonic tissues to be assessed as a particular case of carcinogenesis, that by etiology, pathogenesis and prognosis should be considered individually” [15]. However, the author of the work doesn’t go beyond these recommendations.

In the literature of the following years we haven’t found any attempts to provide this phenomenon with any theoretical interpretation either. Although in our opinion it suggests the existence of some intrinsic cause for transformation of embryonic cells into malignant ones. It is unclear whether this cause can have any relationship to other cases of carcinogenesis. It can’t be excluded that determination of the nature of this intrinsic factor and induction of neoplastic transformation will enable one to find answers to some other questions as to the mechanism of malignant tumors origin.

About 30 years ago G. Svet-Moldavsky [9] explained this phenomenon as follows: in embryos there exist some powerful cellular and humoral factors regulating the embryonic cells capacity to grow and differentiate. They are absent in an adult organism. If embryonic cells are reproduced in the organism where there are no factors regulating their growth and differentiation, they’ll become malignant.

In a theoretical study “Embryonic Properties of Tumor Cells: Facts and Hypotheses” Ya. Ehrenpreis [18], touching upon the problem of extrauterine embryonic grafts’ neoplastic transformation, points out, that the reason for it is non-embryonic conditions of such grafts cells’ existence but he doesn’t specify what factor of these conditions exactly is directly responsible for neoplastic transformation. And on the basis of his monograph “Contemporary concepts of tumor growth” [17] only, published in 1987, does it appear that he, like G. Svet-Moldavsky as well, sees the reason for such transformation in the absence of embryonic inductors of differentiation in the adult organism. Such ideas are quite logical. Actually in embryos normally not only does the growth and differentiation of embryo’s own cells occur but so does the differentiation of cancerous cells transplanted into the embryo [30]. However the blank side in these hypotheses is the fact that many attempts to isolate the differentiation factors out of embryos yielded no convincing results. Embryonic extracts, being not infrequently far from inhibiting, have even stimulated neoplasias’ growth.

But rightful can also be another assumption, viz.: in adult organisms there’s a certain factor that induces malignant transformations of embryonic cells which is absent in embryos. What kind of factor can it be? One of the distinctions between embryo and an adult organism is the presence in the latter of the immune-reacting system and its absence in embryos. So, perhaps, the very system itself contributes to the fact that cells, having embryonic properties, become malignant while being transplanted into an adult organism? We are aware of some paradoxical character of such an assumption since usually the effects of an entirely opposite nature are associated with the immune system, as It is the one, which, in compliance with the theory of immune surveillance, resists the development of malignant neoplasms. Nevertheless, it is well known that immune reactions in an organism are being far from playing always a protective role. A lot of examples can be given to show that they are an important and sometimes even a key factor in the development of diverse pathologic processes, severe ones included [6].

Let us regard some other arguments speaking in favor of our assumption. Let’s begin with the most principal one. A number of embryonic cellular markers include substances of protein nature with inherent antigenicity in an adult organism in auto- and syngeneic systems. Therefore the embryonic cells that happened to get into the adult organism will be subject to the action of various effectors of the immune system. And this impact will undoubtedly have certain consequences for embryonic cells, that will be manifested if not in their destruction but then in some serious functional disorders, for instance, in differentiation disturbances. Thus the immune reaction seems to be capable of acting as a destabilizer of the situation. We don’t see any other candidates for this role to play.

Let us word this hypothesis as the following postulate: the factor, transforming embryonic ectopic grafts into malignant ones in adult animals in syngeneic system, represents an organism’s specific immune reaction. Let’s consider further on, whether this postulate can be applicable to the cases of carcinogenesis occurring under natural conditions and can be modeled in the experiment, viz.: to blastomas, induced by diverse carcinogenic impacts, as well as to the tumors of viral origin and to spontaneous tumors.

Let us refer again to Ya. Ehrenpreis’ views on carcinogenesis[17]. According to his ideas normal embryonic cells are initially endowed with neoplastic potencies that are realized in the form of malignant growth when embryonic cells happen to get into non-embryonic conditions of their existence; tumor cells are embryonic cells, devoid of the posibility to participate in normal embryogenesis. As for somatic cells, giving rise to tumor growth, they gain embryonic properties and, consequently, also a potency to neoplasia during the latent period of carcinogenesis. Since embryonic properties, in this case, are transferred to cells, not designed for embryogenesis, their further existence is manifested as tumor growth.

If we consider somatic cells, embryonized under the impact of carcinogenic factors, as the particular ectopic embryonic grafts, then the above worded postulate may be applicable, in fact, to all of the versions of carcinogenesis. But in that case it seems to come into conflict with oncogene theory, by which the only reason for cells neoplastic transformation is derepression of oncogenes in them and no other conditions for it are required. That is to say the event of oncogenes’ derepression alone is already sufficient for malignant transformation to take place.

To make these discrepancies agree, oncogenes’ functions should be analyzed in detail. Most of the scientists believe that oncogenes play a very important part in an organism (common to all species of living organisms), that of regulating the cells’ growth and their differentiation [4]. Various oncogenes in placental animals are found to be expressed freely in certain periods of their embryonic development and it is quite natural that at this time they are responsible for an organism’s cellular and tissue characteristics, which we call embryonic ones. Oncogenes in the process of an organism’s development are repressed. But if they start functioning in an adult organism, then the products of their activities appear to be immunologically heterologous for the mature organism and a typical immune reaction is developed in respect to them.

Taking into account all the above-stated, the mechanism of malignant process origin is conceived by us as follows. Under the impact of some external or internal factors in organism’s cells there occurs derepression of oncogenes. The direct result of activities of the latter is oncoproteins and other biologically active compounds, embryonic antigens included. In respect to them the organism develops an immune reaction that deforms the vital activity of cells containing activated oncogenes to such an extent, that they lose their capacity for differentiation and get transformed into malignant ones.

This vision of a sequence of events doesn’t deny the oncogene theory, but on the contrary would rather corroborate it as it eliminates the logical difficulty that bewildered many specialists in the field of molecular biology, including such an authority as G. Bishop, who believed that: “What was found in the research, carried out by oncologists, represented the first glimpse behind the veil that had hidden a cancer mechanism for such a long time. What was observed, was in one respect distressing since the chemical mechanisms, that apparently “pushed cells off” onto the pathway of malignant growth, did not differ at all from the mechanisms operating in normal cells” (cited by [10]).

We will cite here one more statement. “The oncogene concept, for all its advantages as compared to other concepts of carcinogenesis, has at least one vulnerable link. Scientists tried to understand how the cellular genes being normal and apparently necessary for the vital activity, when undergoing their minimum alteration (and sometimes, maybe, without any but only as a result of their increase in quantity), become detrimental for the cell and the organism as a whole; what sort of genes are they, without which a cell, on the one hand, is unable to exist and, on the other hand, is incapable to resist their harmful action?” [10].

In accordance with the postulate proposed, the problem of this contradiction can be solved in rather a simple way. Actually, the chemical mechanisms (meant here are oncogenes’ products and biochemical functions, brought about by them) operate in a similar way both in tumor cells and in normal embryo cells. No matter whether oncogenes function in embryo cells or in an adult organism’s cells or even in the cellular culture, the result will be identical. There are no reasons to think that their activities’ products can have different properties insofar as oncogenes’ nucleotide matrix remains one and the same in all the cases shown. The whole point is that the organism’s reaction to the derepressed oncogenes’ products in the period of embryogenesis and in the adult state is different. Therefore it is not the chemical mechanisms as such that trigger tumor process but the organism’s immune reaction “pushes” the cell, embryonized as a result of oncogenes’ disinhibition, off the normal pathway of differentiation.

In this connection it is necessary to consider a well studied phenomenon – the phenomenon of immunostimulation of tumor growth, playing an important role in pathogenesis of malignant tumors. However, today it hasn’t yet been given due attention either. This phenomenon was identified when studying the immune reactions’ impact upon the tumor process. Its manifestations were unnatural and unclear. The reason for immunostimulation was first believed to be some factor, not yet explored, that was even termed as XYZ to emphasize its enigmatic nature. However it was revealed very soon that this factor’s nature doesn’t differ at all from the already known immune reactions.

The facts about the tumors’ immunostimulation have been accumulated and finally an attempt has been made to theoretically construe them. The tumor growth was believed to be enhanced due to the blocking factors that impaired the antitumor action of immune reactants and the tumor cells started to reveal more freely their potential to rapid and unlimited growth. But such a view was radically changed on the boundary between 60ies-70ies, after R. Prehn started working on this subject. At first the results of his experimental works were published followed then by a fundamental theoretical study carried out by him together with M. Lappe [36]. This work showed that it was the direct action of immune system reagents that led to the stimulation of tumor growth. This kind of effect is induced by the impaired immune reaction while the strong one is responsible for the inhibition of tumor growth. Some time later, a series of experimental and theoretical works by R. Prehn and other researchers appeared to add arguments in favor of the theory of tumor growth immunostimulation.

The opposite trends of the weak and strong immune reactions’ action upon tumors isn’t something extraordinary. It represents a well-known regularity consisting in that the small doses of biologically active agents (even toxic ones) stimulate the functions of biological systems while the large ones – inhibit them. A great number of examples can be given to confirm the universality of this principle. Therefore the immune action on tumor cells isn’t an exception. The action of the weak immune reaction upon a tumor will be that of stimulation but with its power being increased the stimulation terminates and the inhibition starts. The arrival of this moment depends on the “stimulation width” (let’s thus term it) of the immune action, i.e., on the range between the power of immune reaction, when the stimulation just begins, and its level when the stimulation is over. In pharmacology corresponding to this notion is “therapeutic range” of drugs’ dosage.

Based upon observations of the tumor growth in diverse versions of the experiment, R. Prehn has worded a postulate by which every tumor in order to be stimulated requires the immune reaction of such a magnitude and character, that is peculiar to it alone [35].

Insofar as the specific immune reaction to the tumor arises and develops gradually, its power will be first small – the stimulation of tumor growth will be observed. Then, despite the increase in this power, the blocking mechanisms (aforementioned) start operating which will restrain this augmentation. Integrated power of the immune reaction in reality doesn’t ever reach magnitudes at which tumor destruction starts. It remains always weak and acts as a stimulator of tumor growth.

In the early 80-ies of the 20th century A. Ageenko and co-authors performed a series of works, the results of which are fundamentally important in terms of our knowledge of the immune reaction role in pathogenesis of malignant tumor growth. The authors put forward their own concept of the role the immune system plays in pathogenesis of malignant tumor growth, the underlying idea of which implies the particular importance of embryonic antigens in the processes of tumors’ origin and progression [1]. On the surface of transformed cells at least two antigen groups were shown to be expressed that mediate a different qualitative result of immunologic interaction between tumors and lymphocytes – immunocytolysis and immunostimulation. The latter significantly exceeds immunocytolysisis in its power and is realized in the line of stage-specific embryonic antigens. The authors arrive at the opinion by which “it can’t be excluded that immunostimulation is the mechanism that triggers carcinogenesis and might afterwards play an essential role in tumors’ progression”[1]. Thus these investigations proved that an organism’s immune reaction to the transformed cells plays an important role.

We consider it necessary to make here a short digression in order to introduce an extraordinary essential specification. We use the definition of “embryonic antigens” in relation to those substances only, that being typical of embryos at the early stage of ontogenesis, start to be expressed on plasmatic membranes of transformed (i.e. embryonized) cells and are immunogenic in autochthonous hosts and syngeneic systems, and also activate T-lymphocytes. It is important to emphasize this as the term “embryonic antigens” is used widely enough in relation to a number of substances that don’t generate any immune reaction in hosts nor do they activate T-lymphocytes. These are, for example, α-fetoprotein and carcinoembryonic antigen that aren’t actually the specific markers of tumor process, but the markers of proliferation alone. The importance of this circumstance was emphasized by J. Coggin [22], who indicated two antigens, in particular, which were expressed in embryos and malignant tumors only and couldn’t be identified in any other normal tissues by means of the most high-sensitive technique. These are glycoproteins with molecular masses of 44 and 220 kDa.

The fact, that such embryonic antigens have been identified in all the tumors studied, without regard to the source of their origin (ecto-, endo- or mesodermal) and a species-specific belonging of the hosts (human, rodents) [22-24,39] suggests the presence of universal features in malignant tumors. If we take into account this circumstance and an extraordinary limited quantity of these features, then, finding the method to appropriately affect them, would make it possible to work out a unified approach to malignant tumors’ treatment.

Returning to the main subject of our study, we may state that an organism’s specific immune reaction in respect to malignant tumors is protective only in theory. In reality, it is one of the initiating factors of neoplastic process and its promoter.

Proceeding from the stated ideas on the mechanism of neoplastic process formation and development, malignant tumors should be interpreted as autoimmune pathology. Richmond and Lisa Prehn in their article “Autoimmune Nature of Cancer” [38] wrote the following: “Since the immune reaction facilitates oncogenesis by MCA, MCA- induced cancer can legitimately be termed an autoimmune disease”. In this, the authors consider the MCA system isn’t likely to be a unique one. Therefore they believe that when it becomes known how to prevent autoimmune diseases, it will be possible just as well to prevent not only the development of MCA-induced cancer, but also the majority of malignant tumors. A. Ageenko and V. Yerkhov single out an autoimmune constituent of carcinogenesis too [1].

We, as distinguished from the many researchers mentioned, believe that the immune system not just stimulates the neoplastic growth, but we also substantiate the statement, that it is a malignisative factor for cells, expressing embryonic antigens; that it is the immune system that plays a key role in the mechanism of malignant process formation and development. The significance of diverse carcinogenic effects comes thus to their capability to derepress oncogenes at that time, when a highly powerful system of non acceptance for their products has been already formed, namely, the immune system. It provides more grounds to speak of the malignant tumors as a variety of autoimmune diseases.

Let’s now have a look at the other versions of carcinogenesis and the experimental schemes to fight the tumor growth in light of our postulate. Let’s dwell at first upon the general theory of cancer by A. Cherezov [13] according to which the reason for malignant tumors origin lies in the tissue homeostasis’ disturbance. In correspondence to the author’s ideas the structure of tissue homeostasis consists of the various tissues’ stem (cambial) cells having a high proliferation potential as well as all the signs of embryonality (autocrine stimulation of mitoses, unrepressed oncogenes). These cells ensure the renewal of the bulk of tissues’ specific cellular elements that gets diminished as a result of natural deterioration and destruction. The strictly measured functioning of stem cells, which corresponds to the scopes of natural losses in the deteriorated differentiated cells, is ensured by the mature cells’ capability to produce substances, (chalones), having the property to inhibit the cambial cells’ proliferative impulse. Under the action of various carcinogenic substances there occurs disarrangement of feedback mechanisms and the cells’ proliferation process begins to prevail. Many young cells that have no time to differentiate are accumulated in tissue and there occurs the tissue embryonization. As a result, the tissue homeostasis structure and also then its function are destroyed and a tumor originates. But it remains unclear when the moment comes for the accumulated aggregate of young embryonized cells to cease being the normal tissue and to be transformed into a malignant one. We don’t find any answer to this given by the author of the research. If viewed from the standpoint of the postulate under consideration we will see the answer to it lying right on the surface. The embryonization process of proliferating tissue won’t go beyond the frame of the normal phenomenon until a certain amount of stem cells that are being reproduced and express embryonic antigens, reaches the critical mass, capable of becoming an object of reception by an organism’s immune system.

Immunologic recognition is known to take place only in that case when the cells, bearing heterologous antigens, make up a group of no less than 105 units [5], while the tissular conditions don’t impede it. The immune reaction that follows, imparts a malignant phenotype to the cells. It is this very moment that is crucial in the origin of neoplasms in all the versions of tissue homeostasis’ disturbances.

Proceeding on with the discussion of the postulate, let us refer to the classic experiments conducted by B. Mintz to obtain allophenic chimeras [30]. The allophenic chimerism of healthy and full-value animals emerged in these experiments as a result of inoculating into the blastocyst of mice of one line the teratocarcinoma cells, derived from the animals of another line which had clear-cut phenotype distinctions from the first one in the form of black fur coloring as well as some biochemical markers. In the mice produced from the blastocyst with the inoculated malignant tumor cells, the tissues and organs (right up to germinal ones) were built of the maternal organism cells and of the inoculated malignant tumor cells that lost their malignant phenotype and were involved in normal embryogenesis.

Teratocarcinomas are known to be obtained by inoculating the embryonic cells of an embryo of pre- implantation stages of its development into the so called immunologically preferential sites (anterior chamber of the eye, testes, subcapsular space of the kidney and others), wherein there are conditions of relative immunological tolerance. Manifestations of the immune reaction can be observed in these sites too though in an impaired form [15]. This immune reaction appears to be sufficient to impart malignant phenotype features to the inoculated embryo cells. Further on, these cells (being already malignant ones) are passaged on mice in the form of ascitic teratocarcinoma, i.e., they are always placed in non-embryonic conditions where they are recognized by the immune system and are perceived by it as foreign ones. Before being used by B. Mintz in her experiments such teratocarcinoma cells have previously gone through 200 passages in the form of a malignant phenotype. But once they happened to get under the conditions of a developing embryo they immediately lost their malignancy. This suggests the fact that a malignancy sign in this case is not associated with the stable genic aberrations, but is shaped by the environmental conditions where the main point is the presence or absence of an organism’s immune reaction. Consequently, the embryo cells being exposed to an organism’s immune reaction are transformed into malignant ones, while the malignant cells, when getting under the conditions of normal embryogenesis (with no immune reaction present), become normal and capable of being involved into the normal form-building process.

In the midst of the 70-ies of the 20th century in the Institute for Oncology Problems Acad. Sci. UkrSSR, investigations were carried out, the results of which were consonant with the experimental data, described by B. Mintz. When cultivating in diffusion chambers under the conditions of a healthy animals’ organism the Shwets erythromyelosis cells of rats, featured by non-differentiated blast elements of myeloid and erythroid series, M. Baranovsky [3] observed their differentiation, that over 13 days’ period of explantation in the red branch of hemopoiesis was completed with the appearance of nuclear baso-, polychromato- and oxyphile erythroblasts, but in myeloid- monocytic branch of hemopoiesis – with the appearance of final functional (phagocyting macrophages) and morphologic (segmented granulocytes) forms. Thus, suffice was it to place leukemic cells, by means of a diffusion chamber under the conditions of isolation from the organism’s immune system (it being represented by its cellular elements only) that their differentiation started to occur. However the results of these experiments have never been analyzed in this aspect.

It will be expedient to mention here the findings of several studies that obtained evidences to the effect that malignant tumor cells, being inoculated into embryo, don’t give rise to neoplastic process. So, taking into consideration a generally known fact of the absence of spontaneous tumors in higher animals at early stages of embryonic development, A. Savinska [8] cleared up the question as to whether implanted tumors would grow and develop in embryos in different periods of their intrauterine development. Sarcoma cells’ suspension N16 in physiological solution or Ringer solution with carmine, added for control, was injected through the uterus wall into rats’ embryos. 282 rats (2204 embryos) were operated. 172 embryos (36 rats) were brought to the end of the experiment. Sarcoma, inoculated into embryos at the last third of their intrauterine development, grew and developed both in newborn rats and in female-mothers. When inoculating sarcoma to embryos at the first two thirds of their intrauterine development, tumors were developed in females only. The newborn little rats remained entirely healthy. The tumor failed to have taken on in anybody out of 19 embryos at this period of intrauterine development. Origination of tumors in all the cases of pregnant females after inoculating the tumor material into embryos suggests that the material was living and virulent. A.Savinska’s experiments were repeated by M. Whisson [42] with implanted Iosid sarcoma of rats – no tumors emerged in anyone of 72 embryos that had undergone operation.

Similar experiments were also conducted by B. Tokin and M. Aizupet [12]. Jensen sarcoma cells’ emulsion was injected into rats’ embryos (from 9 to 12 days of pregnancy). Little rats at the age of one week and adult animals served for control. Out of 172 fetuses born who were inoculated with tumor suspension in the period of their embryonic development, only 11 (6,4%) developed tumors. In control animals tumors have been taken on in 80% of cases.

Tumors’ non-inoculability in embryos of the first two thirds of pregnancy in experiments, conducted by A. Savinska, M. Whisson and B. Tokin, can be easily explained from the standpoint of our postulate, that is, by undeveloped immune system in embryos and, therefore, by the absence of its action upon tumor cells.

The degree of success of malignant tumors implantation into embryos of both young and adult animals coincides in terms with the stages of formation of their immune system. Unfortunately, the state of the inoculated tumor material was not studied further on in the above experiments.

Thus the main stages of carcinogenesis, in our opinion, may be considered as follows:

1. The initial material for malignant neoplasms is cells, expressing embryonic antigens.
2. Such cells might emerge in an organism either as a result of oncogenes’ disinhibition under the impact of various carcinogenic factors or as a consequence of tissue homeostasis’ disturbances, during which the disturbance in balance between cells’ proliferation and differentiation occurs with the predominance of the first one. In case of a long-term character of proliferation process and increase in the imbalance mentioned, there may be a local accumulation of a significant amount of young (stem, committed) cells having embryonic characteristics.
3. Such cells, according to the existing views [5], are exposed to the effectors of an organism’s natural resistance system, capable of recognizing small amounts of aberrant cells, right up to the isolated ones. A considerable number of these cells may be destroyed but some amount of them is preserved evading cytolysis.
4. The next stage in the development of tumor process is the formation of a cellular conglomerate out of the cells, having survived after the “attack” of the organism’s natural resistance system, of no less than 105 cells — a critical mass that can be recognized by the receptors of a specific immune reacting system.
5. After the immune reception of antigenic determinants of accumulated cells’ has occurred the stage of formation of an organism’s immune reaction to those determinants its action upon the cells which finally calls forth their malignant transformation.
6. Since this moment an antagonistic interaction originates between the organism and tumor cells, that is manifested in the form of tumor disease with all the variety of symptoms, during which progressive tumor growth is continuously supported by the immune stimuli.

Malignancy of the neoplastic process flow depends, on one hand, on how strong are the tumor cells’ potencies for the progressive growth (as a rule, the less differentiated are the cells, the higher are these potencies); on the other hand it depends on how the character and the power of an organism’s immune reaction in respect to the tumor correspond to that level of this reaction at which its strongest tumor-stimulating effect is observed.

Summing up all the above-stated we come to the following conclusion: irrespective of the nature and kind of carcinogenic factors as well as the circumstances of their action, a cellular conglomerate expressing embryonic antigens is shaped in an organism, sufficient in quantity for its reception by the organism’s immune system. It is the impact of the immune system effectors upon this conglomerate that is responsible for its gaining the properties of a malignant tumor and for a further promotion of its growth.

Thus, the specific organism’s immune reaction is unable to realize that kind of action, on which so much hope was once set. Under the natural conditions, it realizes just the opposite function, bringing about the formation of a malignant tumor process and promoting its development.

Contemporary oncology has two alternative directions to solve the problem of malignant tumor growth. Both the first and the second ones are science-based and have a perspective for achieving favorable results. The main idea of the first one consists in striving to radically eliminate tumor cells wherever they may be [7]. Nowadays tremendous intellectual and material resources are turned to the development of this direction. Another direction is based on the data, according to which malignant tumor cells retain their potential capacity for differentiation [11, 15, 33]; it provides for the possibility to create conditions for retransformation of malignant cells into normal ones (it’s in an ideal case) or to achieve partial rise in the grade of tumor cells’ differentiation, resulting in their malignancy decrease [14]. Advantages and attractiveness of such a direction are indisputable. It is this second pathway where we see the prospects for our ideas to be developed.

We believe that the transformed cells’ capacity for differentiation may be realized, on condition, that the factor impeding it, i.e., an organism’s immune reaction to tumor antigens, the embryonic ones in particular, has been eliminated.

Analyzing the problem of malignant tumor growth under some other aspect, M.G. Baramiya arrived at the similar conclusion: to overcome the disintegrated (i.e. malignant) growth it’s necessary to induce and maintain in a tumor-host a status of absolute immunologic unresponsiveness to the transformed phenotype [2].

We regard all the above-stated as substantiation of a fundamentally novel immunological approach to malignant tumors’ treatment, and the previous experimental findings corroborate the productivity of this idea.

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