PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. The Discredit of Cancer Metastasis by Sergey N. Rumyantsev, M.D., Ph.D., D.Sc. Summary The present article is devoted to try and revise two main myths of contemporary oncology based on well-known data about cancer manifestations in the light of recent all-pathological and genetic discoveries. The hypothesis is that potentially cancerous cell clones appear in the body as a result of crossbreeding between persons with partially different genomes. The clones exist in the body before postnatal ontogenesis, and for many decades exist as multiple, stochastically distributed cell populations in full concordance with general rules of cell reproduction and tissue growth. But, at a certain age (mainly after 40 years of age), according to specific programs of ontogenesis, the clones begin malignant development induced by a set of unknown events. The cells become constitutionally immune to normal regulators of cell reproduction and tissue growth, thus initiating the malignancy. Introduction Cancer or malignant disease is the second most common cause of death in many developed countries. In the USA, for instance, cancer accounts for 1 in 4 deaths. It is exceeded today only by heart disease. Moreover, the cancer incidence continues to rise. Despite considerable epidemiological, immunological, genetic, surgical and pharmacological efforts, cancer continues to increase its role in human death. The amount of knowledge about the origin and causes of the disease is far from satisfactory and full of myths, including both the compulsory existence of maternal (primary) tumors and the inevitable spread (metastasis) of cancer cells from maternal tumors to form new (daughter) tumors in distant locations in the body. Distant-site metastases are considered the leading cause of cancer-associated mortality. The present article is devoted to try to revise the two main myths of contemporary oncology based on well known data about the cancer manifestations and course1 in comparison with the data of recent all-pathological, epidemiological, immunological and genetic discoveries. The hypothesis is that potentially cancerous cell clones appear in the body as a result of interbreeding between persons with partially different genomes. The clones arise in the body before postnatal ontogenesis, and for many decades exist as multiple, stochastically distributed cell populations in full concordance with general rules of the regulation of cell reproduction and tissues growth. But, at a certain age (mainly after 40 years of age), according to specific programs of ontogenesis, an unknown event induces malignant development. The cells become constitutionally resistant to normal regulators of cell reproduction and tissue growth, thus initiating the malignant development. All-pathological prerequisites According to the general theory of pathology, despite the differences between existing diseases, there is a set of striking similarities that unites all diseases without exception. Besides very specific and extraordinary manifestations any disease displays, it also shows universal signs that are characteristic of any other disease. Each of these features illustrates the all-pathological phenomenon of heterozygous mosaicism created by genetic admixture. Mosaicism is a condition in which the phenomenon of heterozygosity reveals genetically determined variations in pathological manifestations of any diseased state in the level of species, populations, organs, tissues, cells and molecular make-up of individual bodies2. The mosaic composition of living beings arises as a result of heterozygosity. It reveals itself especially intensively in any form of both infectious and noninfectious pathology, determining individual differences in the manifestations, course and severity of diseases. This kind of biodiversity arises as a result of sexual self-reproduction, followed by hybridization between two genetically different organisms: one of them is constitutionally immune to relevant ecological or physiological agents; its mating partner is constitutionally sensitive to it. The hybridization forms inevitably either this or that grade of heterozygosity, which results in the coexistence, in the body, of two active allelomorphic genes and of two allelic cell clones. Both of these alleles function dominantly. As a result, the cell populations of the descendant's body are formed under control of two codominant allelomorphic genes. The heterozygous individual shows both alleles expressed equally but in separated sizes and locations around the body2. The uniqueness and ordinariness of cancer Like any other disease, cancer is also very specific in its origin and manifestations. On the contrary, unlike other kinds of diseases cancer arises when the dividing, growth and differentiation of cells in parts of the body tissue become uncontrolled and crazed. Cancer occurs when some tissue cells become abnormal and divide without control or order that is determined by constitutional (genetic) immunity of involved cells to molecular physiological regulators. Thus, the list of cancer uniqueness is far shorter than that of its ordinariness. On the other hand, like any other disease, the malignancies are characterized by the same set of universal all-pathological signs. This set includes the following intrinsic features:
Each of these well known signs contains contradictions to the revised myths. Genetic immunity to molecular physiological regulators The human body is provided with a physiological system that maintains its structures and functions within their genetically predetermined locations, shapes, sizes and molecular performance. The system acts through molecular physiological mediation, i.e. by means of hormones and other molecular physiological agents. For instance, any dysfunction can be attributed to a deficiency of relevant hormone production. The same result can be achieved by a mutant modification of both the hormone and its receptor, which forms an incongruence between the coactants, i.e. constitutional immunity to hormone influence 3-5. The blocking effect of mutant modification of either hormones or their receptors leads to many pathological processes, including obesity6. The immunity of cells to insulin is a major determinant of the decline of glucose tolerance. Similarly, non-insulin dependent diabetes mellitus is characterized by pathological hyperglycemia in the presence of higher than normal levels of plasma-insulin. Likewise, a pathogenic decrease in cell sensitivity to vitamin D3 determines the familiar forms of rachitic, and the immunity of cells to androgens causes the phenomenon of testicular feminization. An analogous resistance of cells to corticosteroids determines the pathogenesis of Cushing's disease 6. The immunity of cells to thyroid hormones determines the genesis of a range of relevant disturbances. This resistance is an inherited inability to respond appropriately to the T3 hormone linked to mutations in the thyroid hormone receptor (TR)-beta7. The principles of cell immunity to physiological agents are analogous to those ones in the constitutional (genetic) immunity to infections2. In the case of cancer, the work of this precise and powerful system becomes specifically disturbed. The set of such data allow us to put forward a new idea about molecular pathogenesis of cancer. The proposed molecular pathogenesis of cancer Humans are extraordinarily diverse in their manifestations of cancer. Affected people have many individual differences in manifestations of their cancer, as well as in the grade of its expression. The shape, location, size and rate of cancer progression may be different in different individuals or in different organs as well. With the exception of total affection of the body that is only observed in leukemia, multiple myeloma and lymphoma, several areas of restricted, focal, cancer locations exist in most other kinds of cancer. In most cases, cancer is presented by focal manifestations of individually different grades and locations1. The focalization of affections is the principal feature of any disease including cancer. One can suppose that within any body affected by cancer there are initially at least two co-existing clones of homogenous cells with opposite predisposition to the development of the disease. The potentially cancerous clone exists in a form of distantly separated populations and their initial sizes are different and very small. One should suppose that their dispersion around the body has been performed before postnatal ontogeny8 either stochastically or in a manner that is not yet understood, like congenital small dark spots on human skin known as moles, the melanocytic nevuses, that exist in a form of benign neoplasm but may be at a higher risk for melanoma9. Different locations of potentially cancerous clones begin to be visually detectable in different times after initiation of their malignant growth that allow for the supposition of differences in their initial sizes. The differences in initially smallest sizes of such cancer cell masses and their dislocation around the body predestine individual diversity in the course and severity of cancer when the disease begins its development. Most cells of a cancer clone are mainly located in the organ or tissue of their origin. Other locations of the same clone are distant from the origin. Some patients have a cancer whose site of origin is hidden and never identified. Different organs can serve the places for distant parts of a cancer to occur (the lungs, liver, brain, bones, et al). The populations of malignant cells that formed leukemia, multiple myeloma and lymphoma are usually not localized but dispersed around the body like normal cells of the same tissue. Relevant cancer cells may be found in the blood, several lymph nodes, or other parts of the body such as the liver and/or bones1. All locations of a cancer consist of cells similar to those in the organ or tissue of origin. This feature is paradigmatically considered as a result of metastasis1. In contrast to the paradigm it can be considered as a result of a process that still has yet to be understood. Consider the process of innate translocation, i.e. a transfer of a chromosomal segment to a new position, when a part of a chromosome is transferred to another chromosome especially on a non-homologous chromosome. Translocation can result in serious congenital disorders like sarcomas, leukemia, dysplasia, et al. For many decades the initial potentially cancerous cells exist in the body in full concordance with general rules of the regulation of cell reproduction. At a certain age (mainly after 40 years), probably according to specific program of cell population ontogenesis, an unknown event induces their malignant development. Undoubtedly, before the induction began, the cells become constitutionally resistant to normal regulators of both cell reproduction and the growth of cell populations inside of tissues. Cell transformation leading to the emergence of constitutional immunity against relevant physiological regulators should be considered as the first step to malignity. Although it is now an obvious truism that a person's genetic makeup has a principal influence on the development of cancer, the special characteristics of the genome that determine the resistance of cancer cells and focal distribution of cancer around the body are unknown. In contrast, the origin of analogous features of infectious diseases and many noninfectious ones, as well as the role of constitutional immunity in their pathogenesis, have been deciphered recently by many investigators2. The predilection to cancer The existence of genetic predilection to cancer is a most important source of doubts in the reality of metastasis. The predilection is predetermined by a set of genetic factors associated mainly with genetic admixture and with genesis of aging. Genetic admixture (also called xenogamy, outbreeding, cross-fertilization, crossbreeding) refers to the reproductive union of genetically dissimilar or unrelated organisms within the same species that resulted inevitably in the offspring's heterozygosity of various kinds. The states of heterozygosity are responsible for the origin, manifestations, course and severity of most diseases, both infectious and non-infectious2. Increased incidence of most diseases depends on the intensity of the population's genetic admixture. For instance, the number of obese people first began to increase in territories with ethnically-mixed populations6. The role of xenogamy in the origin, manifestations and course of malignant diseases is evidenced by a plethora of epidemiological and clinical observations and investigations. African Americans are more likely to die from cancer than any other racial or ethnic population. In contrast, Hispanics, Asian Americans and Pacific Islanders have lower incidence rates than whites for the most common cancers. The frequency of colorectal cancer varies around the world. It is common in the Western world and is rare in Asia and Africa1. The cancerous insertion in the genome of humankind could happen on the yearly stages of anthropogenesis as a result of interspecies genetic admixture. This highly pathogenic insertion has not been eliminated by natural selection probably because it begins to function at the end of reproductive age. Although only one cancerous clone usually exists in an affected body, the subsistence of a number of such clones is documented too. Approximately one third of cancer survivors aged >60 years were diagnosed again with another cancer. In a population of a developed country with high survival rates, multiple cancers comprise two or more primary cancers occurring in an individual that originated in a primary site or tissue and are neither an extension, nor a recurrence or metastasis10. Cancer patients have a 20% higher risk of new primary cancer compared with the general population. As the number of cancer survivors and of older people increases, occurrence of multiple primary cancers is also likely to increase10-14. Conclusion The mutual exposure, analysis and evolutionary comprehension of epidemiological, clinical, immunological, genetic and experimental data concerning principal characteristics of cancer showed that many of them are also common in those of many other kinds of diseases. Cancer is determined by a constitutional immune incongruence between relevant molecular cytoecological agents and their molecular targets. These features of individual molecular constitution exist in a population as a result of genetic admixture between people evolved in ecologically distinct environments and are different in their molecular constitution on the level of cytoecological regulators of cell growth, development and differentiation. Individual and intra-individual diversity in the cancer course, including the manifestations and severity of specific affections, their sizes and focal disposition around the body, could be created by inter-ethnic mating of persons with different grades of regulator-receptor incongruence. Thus, according to the hypothesis formulated and examined above, the genesis of cancer and its spread in a population are associated with both evolutionary formation of inter-ethnic differences and genetic admixture. The restriction of genetic admixture could be a most effective way to prevent the growth of cancer incidence. What are the tests for the existence of cancerous genetic admixture that should be elaborated and used tomorrow? References
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