Highlights of the Theory | Cancer is a "Bad Embryo"

For the first time the Theory provides a comprehensive explanation of the following key characteristics of cancer:

malignant reprogramming of somatic cells into cancer stem cells,
immortality of cancer stem cells,
heterogeneity of malignant tumor cell populations,
ability of cancer stem cells to spread within body tissues and to develop metastatic tumors,
malignant progression,
selectivity of host immune tolerance to cancer cells.

Explanation of biological essence of malignant transformation of a mortal somatic cell into immortal cancer stem cell:

The crucial genetic event leading to malignant transformation of a somatic cell is its reprogramming: the switching over of its “somatic cell’s genetic program” to the “germline cell’s genetic program”. This means that like an immortal germline cell a cancer stem cell realized its potential immortality by performing of its life cycle.
A cancer stem cell is a somatic cell reprogrammed into a mimic germline cell. During malignant transformation of the somatic cell nothing happens with it except its “germinalization”. Therefore we named the cancer stem cell an “oncogerminative cell”.
Oncogerminative cell is the only cell in the body that possesses a unique property to develop a malignant tumor by performing of its life cycle, which mimics a life cycle of germline cell.

Explanation for biological nature and reason of tumor development by immortal cancer stem cell:

The only natural mechanism that secures in vivo the potential immortality of both germline cell and oncogerminative cell is its ability to perform its life cycle to develop multicellular structures: embryo and malignant tumor (mimic embryo) correspondingly.
Nature does not create de novo the mechanism of potential immortality to benefit an oncogerminative cell. Instead, an oncogerminative cell re-uses a life-cycle mechanism of potential immortality of germline cell along with its fundamental behavior and structures.
A malignant tumor is a mimic blastocyst-stage embryo, developed by an immortal oncogerminative (cancer stem) cell due to accomplishing of its life cycle. Therefore, a malignant tumor is a product of the life cycle of an oncogerminative cell.

We consider the phenomenon of cancer development as a discovered new phenomenon of developmental biology: “desperate asexual self-cloning event”. In mammals this phenomenon manifests by cancer development which represents desperate attempt of cancer stem cell to implement its potential immortality by cloning the host body.
From the standpoint of developmental biology to have a cancer is the same as being pregnant with a “bad embryo”.

The first to describe the stages of the life cycle of cancer stem (oncogerminative) cell:

The First stage – parthenogenetic multiplication of oncogerminative cells. (This stage mimics cleavage-stage embryo)
The Second stage – aggregation of oncogerminative cells and formation of tumor germ. (This stage mimics morula-stage embryo)
The Third stage – tumor germ becomes a tumor spheroid with a heterogeneous cell population, which consists of malignant oncogerminative and oncotrophoblastic cells, and non-malignant oncosomatic cells. (This stage mimics avascular blastocyst-stage embryo)
The Fourth stage – vascularization of the tumor spheroid and its further growth as a vascularized tumor. (This stage mimics implanted blastocyst-stage embryo)
The Fifth stage – disaggregation of oncogerminative cells and it spreading within host tissues. (This stage mimics primordial germ cells migration)

Explanation of malignant tumor cell heterogeneity:

A pre-implanted blastocyst-stage embryo consists of three types of cells: trophoblastic cells of the outer layer, somatic cells and primordial germ cells of the inner cell mass. The direction of cell differentiation is determined solely by the localization of the cell in the blastocyst.
When developing a tumor, cancer stem cell obeys the same biological laws as a totipotent embryonic cell does, when developing a blastocyst.
Therefore, tumor spheroids are supposed to consist of three major types of cells: oncogerminative (cancer stem cells, which mimic the germline cells), oncotrophoblastic cells (which mimic the embryonic trophoblast cells), and oncosomatic cells (which mimic the embryonic somatic cells).

The Theory proposes following definition of malignant tumor:

A malignant tumor is a mimic blastocyst-stage embryo with heterogeneous cell composition which arises from an immortal oncogerminative cell during its passage through its life cycle.

Explanation of the biological nature of metastasis:

Oncogerminative (cancer stem) cell is a mimic primordial germ cell.
Phenotypic property of the primordial germ cells is their ability to aggregate and develop germinative tissue. Subsequently, this tissue disaggregates into primordial germ cells, which migrate to the embryo’s gonadal ridges within a definite time of embryo development.
Cancer stem cells, which mimic germline cells, possess the same basic phenotypic property to aggregate and form cancer-stem-cell-compartments within the tumor. Subsequently, this cell-compartment may disaggregate into cancer stem cells which migrate into host’s target tissues. This migration is known as metastatic spread.
Only oncogerminative (cancer stem) cell is able to develop a metastatic tumor. After settling in host body tissues, a metastatic oncogerminative cell may repeat its life cycle again and give rise to new metastatic tumor.

A circulating oncogerminative cell alone is unable to implant, invade, and to develop a metastatic tumor. Just as a fertilized germline cell creates a blastocyst before the implantation, a circulating oncogerminative cell must first create a multicellular structure (tumor spheroid) in order to proceed with developing the new metastatic tumor.

Explanation of the malignant progression:

After settling in the body tissues, a metastatic oncogerminative cell may accomplish its life cycle again and develops a metastatic tumor that consists of oncogerminative, oncotrophoblastic, and non-malignant oncosomatic cells in ratio which differs from that of the primary tumor. Disaggregation of the oncogerminative cells of the metastatic tumor may occur again, initiating in the same manner a new cycle of development of the next generation of the metastatic tumor with a different ratio of oncogerminative, oncotrophoblastic and oncosomatic cells.

As a result of clonal selection “vehicle”, the ratio of the oncogerminative, oncotrophoblastic and oncosomatic cells may change in favor of the malignant oncogerminative and oncotrophoblastic ones. Progressive decreasing of the fraction of the most differentiated oncosomatic cells in the metastatic tumors of subsequent generations is the essence of the malignant progression. The extreme version of malignant progression is an undifferentiated tumor which appears to consist mainly of oncogerminative and oncotrophoblastic cells.

The first to introduce the concept of “phylogenetic immune tolerance” for the explanation of nature of selective host immune tolerance to the embryonic antigens of early embryo and cancer:

Through evolution, mammals acquired phylogenetic mechanisms, which are repeated in ontogeny, that secure on both local and system levels the development of semi-allograft embryo. This mechanism that underlies selective maternal immune tolerance to the antigens of early embryo we named “phylogenetic immune tolerance”. The essence of “phylogenetic immune tolerance” is the following: through ontogeny the embryonic antigens, which are potentially immunogenic for the host, are expressed by the cells of early embryo for a short period of time. These antigens disappear long before the fetal/neonatal immune system reach maturity. As a result new individuals gain the ability to produce a normal immune response (i.e. antibody production and/or cell-mediated immunity) following exposure to different antigens except of antigens of early embryo. At the time of the subsequent pregnancy, when antigens of semi-alien early embryo are expressed, the memory lymphocytes of maternal host are unable to initiate the cascade of immune response against the early embryo antigens since host memory lymphocytes have nothing to remember about antigens of blastocyst-stage embryo.

Cancer, as a mimic embryo which produces embryonic antigens, usurps the phylogenetic immune tolerance for its own benefit: to escape immune rejection from the host body.

The first was shown that neonatal vaccination with the embryonic-antigens-based vaccines capable of overcoming a natural “philogenetic immune tolerance” to cancer cells and protect body against cancer.

The first to describe common pattern of interaction between host and embryo and host and cancer and formulated general strategy how to fight cancer radically:

Embryo development	Cancer development
I. First Stage
Fertilization, cleavage, developing of blastocyst. Expression of stage-specific embryonic antigens which are potentially immunogenic and susceptible to maternal immune attack. Absence of maternal immune memory to embryonic antigens of early blastocyst-stage embryo.While pre-implantation blastocyst reaches “critical mass” of embryonic cells it develops self-defense mechanisms against maternal immune reaction towards embryonic cells.Blastocyst implantation and its neo-vascularization. The development of fetus begins.	Malignant transformation of a normal somatic cell consists in its “germinalization” and reprogramming into a cancer stem (oncogerminative) cell. In vivo partenogenetic development of the oncogerminative cell into multicellular tumor spheroid, which is a mimic blastocyst-stage embryo.Expression of antigens which are common for cancer and blastocyst-stage embryo, which are potentially immunogenic and susceptible to host immune attack. Absence of host immune memory to the embryonic antigens which are common for cancer and early blastocyst-stage embryo. While avascular tumor spheroid reaches “critical mass” of cancer cells it develops self-defense mechanisms against host immune reactions toward cancer cells. Tumor spheroid neo-vascularization occurs. The in vivo growth of vasularized tumor begins.
II. Second Stage
First immune system shift in embryo-maternal interaction: complex of endocrine, metabolic, and immune changes which underlie maternal selective tolerance to the semi-allograft embryo. Switching on the maternal immune program to preserving of semi-allograft embryo in maternal body. Development of fetus and placenta.	The immune system shift in cancer-host interaction: complex of endocrine, metabolic, and immune changes which underlie host selective tolerance to the malignant tumor (mimic embryo). Switching on the host immune program to preserving of potentially immunogenic tumor in host body. Tumor growth.
III. Third Stage
Postpartum period. Second immune system shift in embryo-maternal interaction: complex of endocrine, metabolic, and immune changes which underlie activation of immune reactivity against remaining trophoblastic cells and its elimination from the maternal body. Switching over the maternal immune program from preserving of “alien” (the embryo) in one’s own body to the program of rejecting of “alien” (embryonic cells) by own body.	In overwhelming majority of cases absence of switching over the host program from preserving of “alien” (tumor) in own body to the program of rejecting of “alien” (tumor cells) by one’s own body. That result in progressive growth of both primary and/or metastatic tumors, which is fatal to the host body. In some exceptionally rare cases switching over the host program from preserving of “alien” in one’s own body to the program of rejecting of “alien” by own body, similarly to one observed in the postpartum period. That may cause spontaneous recovery from cancer.

Embryo and cancer share similar defense mechanisms that protect it against host-versus-graft immune response. In case of embryo such mechanisms are transient and are restricted by the term of pregnancy. Unlike embryo cancer is protected by such mechanisms constantly.
In mammals the resuming of maternal immune response to antigens of placenta in postpartum period is phylogenetically determined since it protects the maternal body against the development of trophoblastic tumor including chorionepithelioma.
In exceptional cases of spontaneous self healing of cancer the switching over from a program of “preserving alien” to the program of “rejecting alien” (similarly to what happens in postpartum period) occurs.

Thus, in order to fight cancer the host body needs help to “give birth” to malignant tumor forcibly. Ideally that means the removal of “critical mass” of tumor combined with the modeling of the second shift of host immune reactivity against remaining cancer cells.

Oncogerminative Model of Cancer Development

The Theory proposed a new Oncogerminative Model of Cancer Development, which explains the set of malignant properties common to all types of solid cancers:

Malignant transformation starts with specific genetic alterations that ultimately lead to a reprogramming of a mortal somatic cell into a potentially immortal mimic germ-line cell which is cancer stem cell.
The malignant reprogramming of a somatic cell lies in its “germinalization”: the switching over of its “somatic cell’s genetic program” to the “germ-line cell’s genetic program” with a subsequent awakening of a dormant tool of its potential immortality. This means that like an immortal germ-line cell a cancer stem cell realized its potential immortality by performing of its life cycle. Therefore we named a cancer stem cell “oncogerminative cell“.
A distinguishing characteristic of any cancer stem cell is its aspiration to realize its potential immortality by passing through its life-cycle and developing a mimic blastula-stage embryo, which in fact manifests in host body as a malignant tumor.
Malignant tumor development is a multi-stage event which includes:
The First stage – parthenogenetic multiplication of oncogerminative cells. (This stage mimics cleavage-stage embryo)
The Second stage – aggregation of oncogerminative cells and formation of tumor germ. (This stage mimics morula-stage embryo)
The Third stage – tumor germ becomes a tumor spheroid with a heterogeneous cell population, which consists of malignant oncogerminative and oncotrophoblastic cells, and non-malignant oncosomatic cells. (This stage mimics avascular blastocyst-stage embryo)
The Fourth stage – vascularization of the tumor spheroid and its further growth as a vascularized tumor. (This stage mimics post-implantation blastocyst-stage embryo)
The Fifth stage – disaggregation of oncogerminative cells and it metastatic spreading within body tissues. (This stage mimics primordial germ cells migration)
Only oncogerminative cell is able to develop a metastatic tumor. After settling in host body tissues, a metastatic oncogerminative cell may repeat its life cycle again and give rise to new generation of metastatic tumor.
A circulating oncogerminative cell alone is unable to implant, invade, and to develop a metastatic tumor. Just as a fertilized germ-line cell creates a blastocyst before the implantation, a circulating oncogerminative cell must first create a multicellular structure (tumor spheroid) in order to proceed with the development of a new metastatic tumor.
Cancer and embryo share similar defense mechanisms that protect it against host-versus-graft immune response. In case of embryo such mechanisms are transient and are restricted by the term of pregnancy. Unlike embryo cancer is protected by such mechanisms constantly.
Cancer is a phenomenon of developmental biology which we determined as a “desperate asexual self-cloning event”. In mammals this phenomenon manifests by cancer development which represents desperate attempt of cancer stem cell to implement it potential immortality by cloning the host body.
From the standpoint of developmental biology to have a cancer is the same as to be gestating with a “bad embryo”.
In order to get rid of cancer the host body needs help to “give birth” to malignant tumor forcibly. Ideally that means the removal of “critical mass” of cancer cells combined with the overcoming of selective immune tolerance toward remaining metastatic cancer cells.

Statements of the Theory

The Theory introduces following novel statements for a comprehensive understanding of cancer:

During malignant transformation of a somatic cell nothing happens in it besides its “germinalization” and reprogramming into a mimic germline cell, which in fact is a cancer stem (oncogerminative) cell.
The synonyms of oncogerminative cell are: cancer stem cell; mimic embryonic stem cell, and mimic germline cell.
Oncogerminative cell is only the cell that possesses a unique property to develop a malignant tumor by accomplishing its life cycle, which mimics a life cycle of germline cell.
When developing a malignant tumor, oncogerminative cell, obeys the same biological laws as an embryonic stem cell does, when it develops a blastocyst-stage embryo.
The Theory introduces the following formula: “The oncogenesis follows ontogenesis that is blocked at the stage of mimic blastocyst which in fact is a tumor spheroid”.
Definition of malignant tumor: a malignant tumor is a mimic blastocyst-stage embryo with heterogeneous cell composition which arises from an immortal oncogerminative cell during its passage through its life cycle. A malignant tumor is a product of the natural life cycle of an immortal oncogerminative cell.
Only an oncogerminative cell is able to develop a metastatic tumor. After settling in host body tissues, a metastatic oncogerminative cell may repeat its life cycle again and give rise to new generations of metastatic tumors.
A circulating oncogerminative cell alone is unable to implant, invade, and develop a metastatic tumor. Just as a fertilized egg cell creates a blastocyst before the implantation, a circulating oncogerminative cell must first create a multicellular structure (tumor spheroid) in order to proceed with a metastatic cascade and to develop a metastatic tumor.
The phenomenon of cancer development is a discovered new phenomenon of developmental biology: “desperate asexual self-cloning event”. In mammals this phenomenon manifests by cancer development which represents desperate attempt of the oncogerminative cell to implement its potential immortality by cloning the host body.
From the standpoint of developmental biology to have a cancer is the same as to be gestating with a “bad embryo”.