Vol.1, No.2, 27-40 (2011) doi:10.4236/oji.2011.12004 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ Open Journal of Immunology Functions of hereditary immunity and xenogamy in cancer origin and pandemic spread Sergey N. Rumyantsev Department of Evolutionary Immunology, Andent, Inc., Jersey City, USA; rumyan1@yahoo.com Received 1 August 2011; revised 18 August 2011; accepted 31 August 2011. ABSTRACT The efficacy of means exploited currently for cancer prevention an d treatment appeared to be very low. New insights into the origin of the di- sease are sorely needed. The present article synthesizes the results from integrative recon- sideration of actual data on cancer from the viewpoint of recent developments in pathology, epidemiology, immunology, genetics, and evo- lution. In contrast to the 80 y ears old hy pothesis of somatic mutative origin of carcinogenesis, the revealed set of evidence showed the origin of cancerous clones is based on inherent con- stitutional incongruence between the regulators of cell physiology and their targets realized in inherent immunity of cancerous cells to normal regulation of cell replication and tissue grow th. The incongruence arises out of both genome mut ations which led to interethnic di fferences in the regulator-receptor structures and inter- course between ethnoses, the regulator-recep- tor evolution of which has been processed to deal with different ecologic conditions. The cu- rrent pandemic spread of cancer is brought about growing expansion of interethnic xeno- gamy favored by growing industrialization, ur- banization, globalization, and migration. The pro- posed hypothesis of genome intrusion in the origin of cancer in duces new research ideas and proposals for cancer prevention and therapy. Keywords: Biodiversity; Cancerous Genealogy; Carcinogenesis; Genomic Mutations; GI-hypothesis; Heterozygosity; Regulator-Receptor System; Self-Reproduction; Somatic Mutations 1. INTRODUCTION Although the rare appearance of cancer disease could happen far long before the descent of human, its written history starts from the very beginning with Egyptian pa- pyrus of around 2625 B.C.E. when the Egyptian phy- sician Imhotep (Figure 1) described “bulging tumors of the breast”. For therapy, he honestly offered only “There is none” [1]. For many subsequent centuries cancer was a not well known disease which killed only some people. It was not utill 1940 that cancer overtook many infectious diseases as an important human killer. Three decades later cancer became one of the biggest threats to global human health that takes a terrible and growing human toll. Thus cur- rent cancer pandemic is the quintessential product of modernity. The War on Cancer, the “cancer crusade” forced by the U.S. National Cancer Act of 1971 provided a massive stimulus for cancer research. The Act made big promises, promoted the U.S. National Cancer Insti- tute (NCI) and gave NCI a token measure of independ- ence. The NCI elaborated strategy of the war based on the existed hypothesis of cancerous somatic mutation of an alone cell and subsequent metastasis of its diseased offspring around affected human body to form secondary (metastatic or dispersed) tumors [2]. Since the 1971 act, National Cancer Institute has spent about $90 billion on science, treatment, and prevention of cancer [3]. Now, 40 years later, the disease continues to spread throughout the globe. The efficacy of means exploited currently for cancer prevention and treatment appeared to be very low. For instance, Provenge, a most recent immune treatment for metastatic prostate cancer costs $93,000 and extends life about 4 months [4]. Really, “There is none” for therapy of cancer. The promises of ‘somatic mutation hypothesis’ appeared to unpaid. Most research and treatment questions that then vexed the cancer community remain unanswered. The initially accepted paradigm of cancer origin and pathogenesis appeared to be impotent. Nevertheless the bankrupt para- digm continues to be kept by experts predicting total U.S. spending on cancer care could rise by as much as 66% to $207 billion by 2020 [5] without any guarantee for rele- vant increase of the investments’ efficacy. Based on the
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 28 Figure 1. Imhotep. First to describe a cancer [1]. hypothesis of somatic mutations and consequent me- tastasis, oncology faces its limits. The search for subtle links between diet, lifestyle, or environmental factors and disease leads to an unending source of fear, but often yields little certainty. Studies on weak associations or small effects often produce contradictory results which confuse the public. A need has emerged to develop a more enlightened paradigm that might capture the most essentials about the cancer. New insights into the origin, pathogenesis and epidemic spread of the disease are therefore sorely needed. There are many observations, experiments and theoretical discoveries to be made in this way. The pre- sent article aims to present the entire set of evidence of the bankruptcy of the ‘somatic mutation hypothesis’ and to promote a systematic search for such new insights which should open new view on the origin of cancer and its pathogenesis, including the dispersion of cancerous cells around the body and forces propelling this process. The article presents the results from reconsidering and re-comprehension of various either direct or indirect data regarding cancer epidemiology, clinical manifestations, and molecular pathogenesis from the viewpoint of recent all-pathological, immunogenetic, genetic, and evolution- nary discoveries followed up to cellular, subcellular and molecular level. The main accent was on the observa- tions of genetic predilection to cancer amongst different human populations, ethnoses, and individuals. Special attention was paid to the revealing of the signs of genetic peculiarities of different locations of cancer around dis- eased body. Over the comprehension of the origin of cancer the last one was considered as an entire phe- no- menon resulted from an entire process. This feature of exploited methodology was considered as condition sine qua non. 2. RESULTS AND DIS CUS SION 2.1. Prevalence of Cancer Although cancer occurs in every country in the world, there are wide ethnic variations in its mortality rates (Figure 2). The rates used are the number of cancer deaths per 100,000 population. They are ranked from the highest to the lowest. The data revealed four-fold differ- ence between the lowest (54.4 in Thailand) and highest (235.4 in Hungary) male cancer mortality rates. The group of five most cancerous countries unites Hungary, Luxembourg, Belgium, France and Uruguay. Amongst a group of five least cancerous countries Mexico, Ecuador and Panama shares their neighborhood with Thailand and Kuwait. One can suppose in contrast to Hungary the population of Thailand could be named innately immune to cancer. The rates of cancer incidence show far more varia- tions [6]. The rates for all cancer sites in males revealed an over eight-fold differences that ranged from 493.8 per 100,000 in Tasmania, Australia, to a low of 59.1 in The Gambia, that shows also lowest rates for cancer of colon, rectum, pancreas, bronchus, lung, thyroid gland, myeloid leukemia, bladder, tongue, mouth and testis. One can expect the key to the origin of cancer will be found in the ecology of The Gambia innate ethnos, which pro- vided him with more than 5-fold resistance to cancer in contrast to the USA blacks and whites. Prostate cancer, one of the most common cancers in men, is more fre- quent in the USA men of African origin. Large variations were observed at primary sites of skin and pancreas cancer (Figure 3). At the same time incidence rates for all cancer sites in African Americans are >1.5-fold greater than rates in European Americans [7] that can be explained by 400 years old genetic closeness between the ethnoses. The largest ratios of the highest rates to the lowest rates in worldwide cancer incidence (Table 1) among
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. http://www.scirp. org/journal/OJI/ 2929 incidence among men ranges from a high of 119.1 in New Zealand Maoris to 1.0 per 100,000 in The Gambia. U.S. black men in New Orleans experienced a lung can- cer rate of 115.9, just lower than that for Maoris in New Zealand. These observations (Figures 2-3 and Table 1) are seen very mysterious in the light of the orthodox postu- lates about the causes of cancer. This is one of the main riddles of cancer manifestations that should be decoded. At the same time, they evidenced the existence of eth- noses (and persons) with very high grades of natural i.e. genetic immunity to cancer and thus reveal very impor- tant milestones in the way to the deciphering of both the origin of cancer and the genetic components of the dis- ease pathogenesis. A more complete understanding of cancer origin, pathogenesis and epidemic spread will come from the discovery of relevant subjects in opposite ethnic and racial groups. One of the mile stones could be the traits of ethnoses and populations which reveal op- posite values of the rates of cancer prevalence. Another milestone could be revealed by the analysis and com- prehension of both individual and intra-individual diver- sity in genetic immunity to cancer. Figure 2. Variation in male cancer mortality rates among dif- ferent populations according to [8]. males were for melanoma of the skin, nasopharynx, and larynx, with ratios of 289, 285, and 204, respectively. For melanoma of the skin, the area reporting the high- est rate was the Australian Capital Territory with 28.9 per 100,000; the lowest rate, 0.1, was reported among Kuwaitis in Kuwait and among persons in Khon Kaen, Thailand. For nasopharynx, the highest rate was 28.5 in Hong Kong while the lowest was 0.1 for Quito, Ecuador. For larynx, the highest rate was 20.4 in Basque Country, Spain, and the lowest rate, 0.1, was for men in Qidong, China. Prostate cancer rates were highest for black men in Atlanta, Georgia (102.0) and lowest in Qidong, China (0.8 per 100,000). The worldwide range in lung cancer 2.2. Unique Features of Cancer Any disease displays a set of universal all-pathologi- cal features that are also character istic of other diseases. The set of universal features includes at least a dozen intrinsic signs: 1) different incidence of a disease among different races and ethnic groups, 2) increased preva- lence of diseases in developed and civilized countries, 3) genetic predilection to the disease, 4) age differences in the disease incidence, 5) stochastic distribution of indi- Figure 3. Electronic visualization of supposed translocation of cancerous cells from primary tumor to distant organ [9]. Openly accessible at
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 30 Table 1. The ratios of the highest rates to the lowest rates in worldwide cancer incidence according to [7]. The values of rates per 100,000 Cancer Highest rates Lowest rates Ratio Skin melanoma 28.9 (Australia) 0.1 (Kuwait) 289 Nasopharinx 28.5 (Hong Kong) 0.1(Ecuador) 285 Larynx 20.4 (Basque, Spain) 0.1 (China) 204 Prostate 102.0 (Atlanta, Ga) 0.8 (China) 127 Lung 119.1 (Maoris, NZ) 1.0 (Gambia) 119 vidual cases amongst a population, 6) individual varia- tions in constitutional (genetic) predilection to the dis- ease, 7) the mosaicism of affections, i.e. intra-individual diversity both in the predilection of different parts of a tissue and in the quantity and sizes of affections, 8) dap- pled distribution of affections amongst a body, 9) mo- lecular bases of genomic and cellular pathogenesis and 10) the identity of involved cells in any locations of spe- cific affections around the body [10]. Each of these universal features expresses the all- pathological phenomenon of heterozygous mosaicism created by genetic admixture arising as a result of hy- bridization between two genetically different organisms: one of which is constitutionally immune to the relevant ecological or physiological agent whereas its mating partner is constitutionally sensitive to it. The heterozy- gosity results in the coexistence of at least two activeal- lelomorphic genes in the offspring's genome. Both al- leles function dominantly and create two allelic cell clones whose subpopulations are formed and distributed in the body before postnatal ontogenesis. The heterozy- gous offspring expresses both alleles equally but in dif- ferent sizes and separated locations around the body. The features and functions of codominant clones may be- come obvious at different steps of ontogenesis [11]. This is a kind of chimerism or cellular mosaicism, the occur- rence in an individual of two or more cell populations of different chromosomal constitutions, derived from dif- ferent parental individuals [12,13]. Genetic admixture (also called xenogamy, outbreeding, cross-fertilization, crossbreeding) refers to the repro- ductive union of genetically dissimilar or unrelated or- ganisms within the same species that inevitably results in offspring heterozygosity of various kinds. The states of heterozygosity are responsible for the origin of spotted mosaic manifestations, individually different course and severity of most diseases, both infectious and non-infe- tious [14,15]. The mosaicism is revealed in genetically determined variations in the location, size and other pa- thological manifestation of any disease. Every human disease is extraordinarily diverse in its manifestation. Affected people may have many individual differences in the manifestations of their illnesses as well as in the grade of expression. Each of these universal traits of pathology belongs to any form of cancer too. The shape, disposition, size and rate of cancer progression are also very different in dif- ferent individuals. However, the origin and development of malignancy reveals some unique features. Firstly, in contrast to any other disease, cancer comes into sight when the division and growth of some cells in some parts of the body become uncontrolled. Secondly, the cancer cells look abnormal under the conventional light microscope. They are considered versions of cells which compose the tissue of the supposed cancer origin, how- ever, light microscopy cannot identify the tissue and site of a malignancy origin [16]. Thirdly, cancer genetics holds some mystery traits which should be taken into account too. 2.3. Usualness of Cancer Genetics Recent genetic investigations revealed a number of apparent paradoxes and alternative views of the traits of cancer genetics [17]. The undoubted genetic predilection to cancer is characteristic of both usual and unique fea- tures that can be observed at any level of the disease existence beginning from ethnic and population ones. Although it is now a well confirmed fact that genetic factors play an important role in all steps of cancer de- velopment and a person’s genetic makeup has a principal influence on the fate of a patient [18,19], very little is known about the special characteristics of the genome that determine the unregulated behavior of cancer cells and their distribution around the body [20]. There is known only a minority of cancer sites that arise as a re- sult of inherited and highly penetrant cancer suscepti- bility genes [21]. In contrast, the genetic principle of analogous distinct distribution in both infectious and most noninfectious diseases has been deciphered [10]. Cancer rates in the Californian population of South Asians, that comprise people having origins mainly in India, Pakistan, Bangladesh and Sri Lanka, are different from those breast cancer observed in other ethnic groups inhabiting the same state. Compared to rates in native Asian Indians, rates of cancer in South Asians of Cali- fornia were higher for all sites of cancer locations. In contrast to Asian/Pacific Islanders of California, the South Asian population experienced more cancers of the esophagus, gall bladder, prostate, breast, ovary and uterus, as well as lymphomas, leukemias and multiple
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 3131 myelomas. Compared to the non-Hispanic White popu- lation of California, South Asians experienced more cancers of the stomach, liver and bile duct, gall bladder, cervix and multiple myelomas. Significantly increasing time trends were observed in colon and breast cancer incidence [22]. African-American women have a lower overall incidence of breast cancer than do Caucasian women, but a higher overall mortality and the differ- ences between their breast cancer cell lines play a role in their different rates of cancer disposition around a body [23]. Recent data of cancer genome sequencing show that almost all the changes in the gene structure of cancer are heterozygous and present in nearly all the cells in the discovered tumor samples [24]. This indicates both the sameness and the unity of cancerous tissue. The malign- nant phenotype is determined largely by early trans- forming events rather than being molded by somatic evolution during the clonal expansion of neoplastic cells [25-27]. Many other genetic findings also confronted the somatic mutation theory with a number of apparent and alternative views [17]. The genotype of cancerous cells is not identical to those of normal ones. In contrast to a well-known fact that vast diversity of normal cell phenotypes in any liv- ing body is generated by the same genome the initiation and development of cancer is influenced by the inherited cancer-promoting genotype [28,29]. Because it begins to function at the end of reproductive age, this highly pa- thogenic genotype has not been eliminated by natural selection. 2.4. Specificity of Cancer Pathogenesis Cancer presents a group of malignant diseases character- ized by abnormal reproduction of some cell clones and consequent growth of relevant tissues in different parts of afflicted bodies. At least four different kinds of such malignancies’ pathogenesis were discovered among hu- man and animals. Firstly, some forms of malignancies arise from infection with specific contagious viruses or bacteria. Secondly, there exists canine transmissible ve- nereal tumor among dogs and analogous contagious cancer among Tasmanian devils [30], sea turtles and sea lion and so on [31,32]. These arose after direct physical intrusion of viable cancerous cells from one host to an- other either over natural sexual contacts or by laboratory manipulations of animals and, occasionally in rare cir- cumstances, over organ transplantation. Sexually trans- mitted tumor of dogs has a worldwide distribution and that probably arose thousands of years ago. Most cases of this form of cancer are eventually rejected by afflicted dog, who then is conferred lifelong immunity [31,32]. Thirdly, there are tumors transferred from mother to fe- tus. And at last, there is cancer of predominant kind that presents one of the biggest and epidemically growing problems in the modern world whose extensive counter- acting efforts appeared to be shamefully impotent. The pathogenesis of this predominant form of cancer is prin- cipally another. Every kind of living being is constitutionally provided with a physiological system that maintains normal body structure within its genetically predetermined shape and size. Special part of this very effective system is dedi- cated to regulate the starting and revival of body struc- tures and their functions on their molecular, sub-cellular, cellular, tissue and organ levels. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old and die, new cells take their place. The regulation is realized on the level of cells and per- formed by means of hormonal molecules. In the case of cancer this orderly process goes wrong. This mighty system of body maintenance appears of being impotent in the relation of some its initially small- est parts. That is happened because cancer is formed by of abnormal cell clone that is able to grow independently of normal physiological control. As a result its cells are forming when the body does not need them whereas some of its old cells do not die when they should. The appeared extra cells form the masses of tissue, called malignant tumors. Two intrinsic hallmarks belong to any kind of cancer. The first and most essential hallmark is absolute resis- tance of cancer cells and tissues to normal physiological regulation of cell growth and tissue formation. The sec- ond hallmark is expressed in the phenomenon of abso- lute immunity of malignant cells and tissues to the de- struction by both cell and humoral mechanisms launch- ing by lymphatic system of responsive immunogenesis that allows cancer evade the surveillance performed by the host’s immunogenic systems. Both the hallmarks perform their obligate functions in the initiation, devel- opment and subsequent progression of any kind of cancer. The lymphatic system of responsive immunogenesis is unable to defend us from cancer’s development. On the contrary, the effective cells of lymphatic system are thought to play an important role in the provocation of carcinogenesis. According to [33] and on the contrary to the hypothesis of somatic mutation the cells may induce malignant transformation of normal cells. Moreover, once cancerous cells develop, an immunoediting process occurs in which immune cells and their molecular me- diators dictate the development and progression of can- cer [33]. Tumor cells also develop several mechanisms to evade anti-tumor immunity by developing an immuno- suppressive microenvironment. The differences in the po- pulations of lymphatic cells infiltrating into tumor tissues
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 32 are associated with differences in clinical outcomes [33]. The underlying molecular mechanisms of the association should be unraveled to get better understanding of the com- plex relationship between tumor cells and the associated lymphatic immunogenic cells. On the other hand, the deficiencies of lymphatic im- munogenic system that are present in the tumor envi- ronment enhance also the progression of the tumor in the host. Such function is thought may belong to the inhibit- tion of natural killer cytotoxic responses, the accumula- tion of myeloid suppressor cells in the tumor, deficien- cies on interferon signaling, the secretion of cytokines that enhance tumor growth (i.e., IL-6, IL-10, CSF-1, TGF-b, TNF), and the expression of surface molecules (i.e., HLA-G, B7-H1, B7-H4, CD40, CD80) that have a role on immune suppression [34]. The process of origin and development of malignancy reveals some unique traits of cancer [35]. Its uniqueness is the abnormality of its cell morphology and aggressive behavior performed by uncontrollable division of can- cerous cells and growth of cancerous tissue. In contrast to any other disease, cancer comes into sight when the division of cells and tissue growth become uncontrolled in some parts of the body. The disturbance is associated with the resistance of cancerous cells to relevant mo- lecular physiological regulators of cell dividing and tissue growth. against growth inhibitory signals. This ability provides them with the capability for unlimited replica- tion and to evade programmed cell death. This kind of specific immunity functions against ecological and phy- siological agents. It is known as hereditary, genetic or constitutional [36]. Hereditary immunity arises in evolution as a result of natural selection performed by life threatening molecular ecological factors of infectious, animals and plant origin. In a case of relevant ecological danger, individuals pos- sessing a mutantly modified molecular constitution ren- dering them incapable of being affected with the agent appear constitutionally immune to a particular agent. They give rise to immune progeny while susceptible individuals of the same species become ill and die without reproduce- ing [36,37]. On repeated exposure of many generations to a given pathogen, the progeny of immune variants even- tually predominate in a population; an individual protect- tive variation becomes the property of a group, then of a population and, finally, of most of a species [38,39]. This kind of immunity is determined by constitutional incongruence between relevant ecological (e.g. infec- tious) regulator and its molecular target in the body. Analogous mechanisms perform constitutional resistance against molecular physiological regulators which are also responsible for many noninfectious diseases. The prince- ples of cell immunity to physiological agents are analogous to those ones in hereditary immunity to infections [10]. Hereditary immunity of cells to relevant hormonal regulators is crucial cause of many diseases. It is created by mutant modifications of either the hormone or its receptor, that forms an incongruence between the coac- tors, i.e. constitutional immunity against hormone influ- ence [40-42]. The blocking effect of mutant modifica- tions of either hormones or their receptors leads to the development of obesity [43]. Genetic immunity of cells to insulin is a major determinant of the decline of glu- cose tolerance. Non-insulin-dependent diabetes mellitus is characterized by pathological hyperglycemia in the presence of higher-than normal levels of plasma-insulin. A pathogenic decrease in cell sensitivity to vitamin D3 determines the familiar forms of rachitic. The immunity of cells to androgens causes the phenomenon of testicu- lar feminization. Constitutional resistance of cells to corticosteroids determines the pathogenesis of Cushing’s disease [43]. The grade of the cells immunity to thyroid hormone determines the range of relevant disturbances. This resistance is an inherited inability to respond ap- propriately to the T3 hormone linked to mutations in the thyroid hormone receptor (TR)-beta [44]. One can note that whereas the cell resistance to hormonal or infectious influences has no visible distinctions from the suscepti- ble ones, the cancer cells look abnormal even under the conventional light microscope. They are considered ver- sions of cells which compose the tissue of the supposed cancer origin, however, light microscopy cannot identify the tissue and site of a malignancy origin [16]. The analogous origin of cancer cells immunity against molecular physiological regulators of cells dividing and tissue growth has recently been hypothesized. The set of above data allowed explain the most unique feature of cancer, its aggressive behavior provided with uncontrolla- ble dividing and growth of cancerous cells. It was sup- posed the physiological uncontrollability of cancerous cells is predetermined by their natural (genetic) immunity to the influence of relevant molecular cyto-ecological regulators of cell circle and tissue growth [35]. This sup- position, together with mutual exposure, analysis and evolutionary comprehension of a set of relevant immu- nological data, allowed put forward a new idea about mo- lecular pathogenesis of cancer. 2.5. Disposition of Cancer around a Body A cancer may exist in an individual body either as alone alien mass (tumor) or as several discrete forms of it. Most cases of cancer are characteristic of severalty, a state of being several and discrete. In the case of discreteness, they may have more than two but not many several parts which appear visually detectable in different times and at different areas of the body. It is taken to suppose that can-
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 3333 cer can dispose in any organ or tissue of the body i.e. that any part of a body are accessible to cancer settlement. The first appeared tumor is called the ‘primary’ tumor. It is usually named for the part of the body or the type of cell among which it appeared. The tumors which arose later are named the secondary, metastatic or dispersed tumors. The last consist of the same type of cells and get the same name as the primary tumor. The list of cancer names is very large. For instance, Muir et al. [45] presented the names as follow: the cancer of lip, tongue, mouth, oropharynx, nasopharynx, esopha- gus, stomach, colon, rectum, liver, gallbladder, pancreas, larynx, bronchus, lung, melanoma of skin, prostate, testis, penis, bladder, kidney, brain, nervous system, thyroid gland, Non-Hodgkin’s Lymphoma, Hodgkin’s Disease, Multiple Myeloma, Lymphoid Leukemia, Myeloid Leu- kemia. There are more than a hundred distinct sites where primary cancers can be disposed either alone or in the combinations with secondary ones. At least two paradoxes can be seen in the disposition of either primary or secondary malignant tumors. Firstly, in contrast to the potential ubiquituosness of primary tumors there are both more favorite and far less favorite sites of their secondary dispositions (Ta bl e 2 ). The pri- mary cancers are mainly disposed at prostate, lung & bronchus, colon, urinary bladder, skin, kidney, rec- tum .pancreas, stomach. Besides, hypopharynx, bones & joints, floor of mouth, nasopharynx, gallbladder, oro- pharynx, oral cavity, trachea, peritoneum and pleura are far less favorable for the disposition of primary tumors. Secondly, in contrast to the potential ubiquituosness of primary tumors there are only some most common sites where the secondary tumors are preferably dispose―the lungs, bones, liver, and brain. Other places of a body are seen far less accessible for secondary tumors. One ques- tion arise immediately―are these unfavorable places immune to the invasion of cancer? The way of living of such variation as well as its reasons have not been dis- cussed anywhere before. Two principal variants for explanation of the reasons of cancer’s discreteness can be today. Firstly, for the last 80 years the prevailing paradigm in cancer origin and pathogenesis was exclusively based upon the “somatic mutation hypothesis” [2,46], which states firstly that any case of cancer is derived from a single somatic cell that has accumulated multiple DNA mutations in genes which control cell proliferation. The mutations are re- sulted in unprecedentedly intensive reproduction of the transformed cell and in the formation of primary tumor inside the affected tissue. It means the disposition of any primary tumor is predestined by the location of maternal mutant cell. The “somatic mutation hypothesis” has also supposed that some maternal cells are able to move (metastasize) outside of primary tumor mainly through the blood- stream or the lymphatic system and form several second- dary tumors in distant locations in the body mainly in the lungs, bones, liver, and brain. The dispersed disposition of cancer cells is paradigmatically considered as a result of their distant translocation (metastasis) from maternal tumor [9]. The explanation suggests that secondary tu- mor can be portrayed as a two-phase process: The first phase involves the physical translocation of a cancer cell to a distant organ, whereas the second encompasses the ability of the cancer cell to develop into a lesion at that distant site (Figure 4). In this way the cells should ac- quire invasive traits, be chipped off the mass of primary tumor, invade toward either blood or lymphatic vessel and after all exit the circulation and invade into the dis- tant foreign tissue. Besides, cancerous cells have diame- ters (20 to 30 μm) that are far too large to allow them to pass through 8-μm diameter bore of capillaries such as those present in the capillary beds of the lungs [9]. The “somatic mutation hypothesis” has also supposed Table 2. Opposite rates of male cancer incidence by primary site and race*(Rates are per 100,000 persons of the 2000 U.S. standard population). *According to [47]. Cancer sites All Races White Black Sites of Highest Rates 1.Prostate 156.9 145.0 226.0 2.Lung & Bronchus 85.0 79.9 95.1 3.Colon 36.9 36.0 46.1 4.Urinary Bladder 36.0 37.9 18.3 5.Skin 25.6 28.0 2.0 6.Non-Hodgkin 22.6 23.1 16.0 7.L-ma 20.8 20.7 23.1 8.Kidney 15.8 15.5 15.9 9.Rectum 13.2 13.0 15.7 10.Pancreas 9.2 8.1 15.5 Sites of Lowest Rates 1. Hypopharynx 1.2 1.1 2.4 2. Bones & Joints 1.1 1.1 0.8 2. Floor of Mouth 0.9 0.9 1.1 4. Nasopharynx 0.8 0.7 1.1 5. Gallbladder 0.8 0.6 1.1 6. Oropharynx 0.7 0.7 1.2 7. Oral cavity 0.4 0.4 0.6 8. Trachea 0.3 0.3 0.2 9. Peritoneum 0.1 0.1 0.1 10. Pleura 0.0 0.0
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 34 Figure 4. Opposite rates of male cancer incidence by primary site and race*(Rates are per 100,000 persons of the 2000 U.S. standard population). *According to [47]. that some maternal cells are able to move (metastasize) outside of primary tumor mainly through the blood- stream or the lymphatic system and form several second- dary tumors in distant locations in the body mainly in the lungs, bones, liver, and brain. The dispersed disposition of cancer cells is paradigmatically considered as a result of their distant translocation (metastasis) from maternal tumor [9]. The explanation suggests that secondary tu- mor can be portrayed as a two-phase process: The first phase involves the physical translocation of a cancer cell to a distant organ, whereas the second encompasses the ability of the cancer cell to develop into a lesion at that distant site (Figure 4). In this way the cells should ac- quire invasive traits, be chipped off the mass of pri- mary tumor, invade toward either blood or lymphatic vessel and after all exit the circulation and invade into the distant foreign tissue. Besides, cancerous cells have diame- ters (20 μm to 30 μm) that are far too large to allow them to pass through 8-μm diameter bore of capillaries such as those present in the capillary beds of the lungs [9]. The existence of first phase is partially confirmed: Large quantities of tumor cells can really circulate in blood and lymph channels but without overt new tumors [48,49]. This may mean at such cases the body does not contain the sites acceptable for realization the ability of circulated cancer cells to develop into a lesion at that distant site (second phase). Except the alone site of pri- mary tumor the whole body is absolute immune to the inception of secondary tumors. The appearance of sec- ondary breast cancer was reported to occur even after 20 - 25 years of disease-free period. After this time, recur- rences were rare, and the mortality rate was no longer statistically significantly different from that of the gen- eral population. Patients surviving to this time without evidence of recurrence or contralateral breast cancer are probably cured [50]. Although metastasis is responsible for as much as 90% of cancer-associated mortality, yet it remains the most poorly understood component of cancer patho- genesis. This process of cancer transposition remains one of the most enigmatic aspects of the disease [9]. It remains hypothesized and mysterious [51]. The tries to envisage the hypothetical process by means of computer graphics [9] create only the illusion of truth but do not change the situation. The somatic mutation hypothesis met recently many questionable assertions about of its main premises. The most questions have been induced by the hypothesis’ supposition about the ability of maternal cancerous cells to move outside of primary tumor and cross several color lines in their ways to the lungs, bones, liver, brain and some other sites where the secondary tumors could dispose. Meanwhile the existence of the process has not been evidenced by observations. In reality we can only observe non-simultaneous appearance of several identical tumors in different parts of a diseased body. Another ex- planation of the reasons and propelling forces of cancer’s discreteness has been proposed and developed just re- cently [35,52,53]. 2.6. The Hypothesis of Genome Intrusion The opposite point of view on cancer origin, patho- genesis and pandemic spread has been presented by ‘the hypothesis of genome intrusion’ (HGI) based on reinterpretation and integrative re-comprehension of main pathogenetic, immunological, genetic, clinical, epidemiological and evolutionary features of the disease [35,52,53]. The emergence of the hypothesis has been predestined by the discovery of a set of uni- versal all-pathological features that include at least a dozen intrinsic signs: a) different incidence of a disease among different races and ethnic groups, b) increased prevalence of diseases in developed and civilized countries, c) genetic predilection to the disease, d) age differences in the disease incidence, e) stochastic dis- tribution of individual cases amongst a population, f) individual variations in constitutional (genetic) predi- lection to the disease, g) the mosaicism of affections, i.e. intra-individual diversity both in the predilection of different parts of a tissue and in the quantity and sizes of affections, h) dappled distribution of affections amongst a body predestined by xenogamous genome intru sion i.e. genetic admixture, i) molecular bases of genomic and cellular pathogenesis and j) the identity of involved cells in any locations of specific affections around the body [10]. Each of these universal signs of pathology belongs to any form of cancer.
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 3535 Besides, it has been hypothesized that any cancerous cell clone is genetically alien, non-self for afflicted body [35,53]. It might appear in the body as a result of genetic admixture led to the intrusion of personal genome with information to control the life of foreign clone which possesses its own deviant genetic programs responsible for the dividing of cells and tissue growth. After that the clone functions according to its own program of onto- genesis including aging. From this point of view any individual cancer should be considered as a result of inappropriate foreign intrusion in a genome under consid- eration. The HGI associates the emergency of cancerous cell clone with the parent’s xenogamy which leads to the formation in the offspring’s body of two coexisting cell clones of similar origin with opposite predisposition to both their growth regulators and the development of malignancy. The almighty lymphatic system of indi- vidual adaptive immunity does not recognize the de- posited cancer cells as foreign and does not destroy them. The inserted foreign clone is not eliminated. This may mean both the emergence of cancerous clone and the dispersion of its subpopulations around the body has been performed before postnatal ontogeny. Separated parts of the clone are stochastically dis- persed around the embryo’s body before postnatal on- togeny by a manner that is used to dispose other embry- onic tissues and organs. After the end of their disposition the populations exist at their stable places like cell masses of smallest but different sizes. After that the clone continue to exists in the body in a form of several distantly separated populations being provided with life supporting stuffs by intruded host. At a relevant time of a breadwinner’s life (mainly af- ter 40 years of its age) the potentially cancerous micro- populations begin to come into sight as hereditary im- mune against prevailing regulators of cell reproduction. The initially largest one of the cancerous micro-popu- lations achieves detectable tumorous size far earlier in comparison to the initially smallest one. The first ap- peared tumor is called the ‘primary’ tumor. The tumors which arose later are named the ‘secondary’ tumors or metastases. Early diagnose and extirpation of “primary tumor” (the first appeared cancer site) may improve me- tastatic progression-free survival but does not exclude subsequent appearance of “secondary tumors” [54,55]. Patient age 74 years was diagnosed with stage III primary breast cancer. The volume of her primary tumor was found to be 10.3 cm3 measured through laborious reading of the whole body PET/CT scans. The tumor was resected. However, 8 years after primary diagnosis and resection, 31 bone, 3 lung, 2 lymph node, and 1 soft tissue secondary tumors were discovered (Figure 5). Volumes of all tumors were measured through laborious reading of the whole body PET/CT scans. In particular, volumes of 31 bone tumors were 1.69, 1.98, 2.01, 2.04, 2.14, 2.20, 2.46, 3.05, 3.18, 3.31, 3.37, 3.48, 3.52, 3.57, 4.22, 4.34, 4.73, 5.04, 5.08, 5.25, 5.45, 5.64, 6.36, 6.55, 7.39, 9.01, 9.21, 11.15, 12.71, 13.81, 22.96 cm3. Addi- tionally, the patient had three lung tumors with the vol- umes 1.30, 2.01 and 7.26 cm3, 2 lymph node tumors with the volumes 2.85 and 9.66 cm3, and one soft tissue tumor with the volume 11.41 cm3 [56]. The researchers revealed also 20 and 15 secondary bone tumors in two other breast cancer patients 5.5 years and 9 months after primary resection, respectively. Be- sides they found the inception of the first secondary tu- mor occurred 29.5 years prior to the primary diagnosis, and resection of the primary tumor was followed by a 32-fold increase in the rate of secondary tumors growth [56]. This may mean the growth of all populations of a cancer is under control performed by their own united physiological mechanism which maintains the whole structure of cancer within its genetically predetermined size. The physiological unity of cancer parts has recently been evidenced by observations on the fate of cancers partially deleted over oncologic surgical procedures. It has been shown the deletion of some tumors by partial hepatectomy initiated proliferation of other parts the cancer has been left after the surgery which resulted in a rapid growth of secondary tumors (“metastases”) in the remaining liver after hepatectomy. Significant increase in tumor growth was found after 70% hepatectomy [57]. Analogical progression of primary and secondary tu- 0―primary tumor at the age 74 years. 1-37―secondary tumors at the age 82 years (1-31―bone tumors; 32-34―lung tumors; 35 and 36―lymph nodes tumors; 37―soft tissue tumor). Figure 5. Volumes (cm3) of primary tumor (before resection) and secondary tumors (8 years after extirpation of primary tumor).
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 36 mors after foregoing resection was also noted in experi- mental [58-60] and clinical [61,62] studies. Partial heap- tectomy impacted on the growth of tumor size in the remaining places of diseased liver. Besides the growth rate of liver’s tumors was more rapid than that of the liver parenchyma. It means their growth rates are regu- lated by different systems. The set of dispersed parts of a cancer functions like an entire self-reliant living being settled in the affected body. That may mean cancers can produce their own growth regulators. Cancer patients have a 20% higher risk of a new pri- mary cancer compared with the general population [63]. As the numbers of cancer survivors and of older people increases, the occurrence of multiple primary cancers is also likely to increase [64-68]. Approximately one-third of cancer survivors aged >60 years were diagnosed more than once with another cancer. Possibly, these variations are associated with the phenomenon of clonal diversity in the genetic programs of the progression of senescence [69]. Such observations prompt the idea of the possible existence of a few potentially cancerous clones in the body [35] and few foreign intrusions in the genome. 2.7. Origin of Cancer Epidemic Four main kinds of malignancies were discovered am- ong human and animals. Firstly, some rare forms of ma- lignancies arise from infection with specific contagious viruses or bacteria. For instance, infection with Rous virus can cause sarcoma among mice. Infection with human papillomavirus can induce cervical cancer among woman. Secondly, the transfer of cancer cells during sexual intercourse spreads canine transmissible venereal tumor between dogs and contagious cancer among Tas- manian devils [30], sea turtles, sea lion and so all [31,32]. Thirdly, tumors can be transferred from mother to fetus, by laboratory manipulations of animals or, occasionally, by organ transplantation. And at last, the cancer of pre- dominant kind spreads among humans by means of ge- nome intrusions over xenogamous self-reproduction. This kind of cancer presents one of the biggest and epi- demically growing problems in the world health [35,53]. The application of above scheme of cancer patho- genesis to the epidemiology of predominant human can- cer can help to explain the leading cancer propelling causes of current epidemic progression. According to the above performed epidemiological and pathogenetic analysis, the carcinogenic functions of genome muta- tions possess important roles in the pathogenesis of relevant forms of the disease. Regretfully, none of such mutations by themselves are able to explain the pan- demic spread of cancer. None carcinogenic mutations could be widely disseminated in the humankind because their rarity, randomness, and to the counteraction of na- tural selection. Thus, the undoubted existence of muta- tive carcinogenesis cannot be used for the explanation of the moving forces of current pandemic spread of ma- lignancy. In contrast, the distributive potencies of xenogamous carcinogenesis are fare more productive. The currently observed increasing incidence of most diseases [63] de- pends on the intensity of the genetic admixture within ethnically mixed populations [10]. Causative function of xenogamy in the origin, individual manifestations and course of malignant diseases is also evidenced by a ple- thora of epidemiological and clinical observations and investigations [35]. African-Americans are more likely to die from cancer then any other racial or ethnic po- pulation. In contrast, Hispanics, Asian Americans and Pacific Islanders have lower incidence rates than Whites for the most common cancers [63]. The frequency of any site of cancer varies around the world. Colorectal site of malignancy is common in the Western world and is rare in Asia and Africa [63]. Although only one cancerous clone usually exists in an affected body, the presence of a number of cancerous clones has also been documented. In a population of a developed country with high survival rates, multiple can- cers often comprise two or more primary cancers oc- curring in an individual that originate in a primary site or tissue and are neither an extension, nor a recurrence or metastasis [68]. Xenogamous forces of cancer distribution could begin to function among humankind at the earliest steps of its evolution. Any evolutionary process is performed by two main propelling forces: mutative diversification in di- versity can be enriched by interbreeding with related populations and species. For instance, the hybridization and exchange of genes between mutual ancestors of chimps and humans may have occurred over period of just a few million years. They may have interbred for a long time after their two lineages began to split apart evolutionarily [70]. Considerable admixture between genomes of Neandertals and early modern Europeans happened near 30,000 years ago [71]. The exodus out of North East Africa and subsequent dispersion around the world over the last 60,000 years has resulted in a wide biological diversification of the species and a strong self-segregation of its tribes from each other. Some tribes moved back to tropical South Africa, the homeland of their predecessors. Other groups migrated in the Euro-Asian or South-Asian ways. Their further evolution was performed by the forces, which propelled biological and social diversification of the species over its dispersion around the world. Inhabiting ecologically disparate geographical areas, migrants con- tinued to evolve independently into five anatomically
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 3737 different races and a multiplicity of segregated ethnic groups [72]. These new ways of life did not favor a xenogamous epidemic spread of cancer, except when seg- regation was broken forcedly, for instance, by aggressive tribes. In contrast, the influence of xenogamy on the dis- tribution of cancer among the members of separated eth- nic groups was restricted. Today, the situation is becoming the opposite. Thanks to growing industrialization, urbanization, globalization, and migration, most urban populations became ethni- cally mixed. The genomes of modern urbanized humans become the mosaics composed of genetic segments in- herited from an extensive row of ancestors has been eth- nically segregated before. The spread of cancer became pandemic, intensified by the growing expansion of xenogamy, the reproductive intercourses between eth- noses, which proceeded at different environmental con- ditions for previous evolution. The currently observed increasing incidence of cancer, as well as many other diseases, depends on the intensity of the population’s genetic admixture promoted within ethnically mixed populations. This kind of pathology is now more char- acteristic of any mixed population. The current pande- mic spread of cancer is intensified by the growing ex- pansion of xenogamy. 3. CONCLUSIONS The above-presented results of reconsideration of the actual data regarding cancer from the viewpoint of re- cent all-pathological, epidemiological, immunological, clinical, genetic, and evolutionary discoveries allowed a new integrative paradigm―the hypothesis of genome intrusion―about the origin and pandemic spread of the disease to be formed. Main postulates of the hypothesis of genome intrusion can be presented as follow: 1) The existence of cancer diseases is predetermined by genome mutations have created inter-ethnic differences in molecular constitution of inherent physiological sys- tems responsible for regulation of cell dividing and tis- sue growth. 2) The development of individual cancer disease is initiated by the appearance in afflicted body of cell clone (or clones) inherently immune to normal physiological regulation of cell growth and tissue formation. The cells of such inherently immune clones are able to grow in- dependently of physiological control of normal cell rep- lication. This clone is foreign (alien, non-self) for af- flicted body with many of its traits. 3) Such inherently immune clones appear in a body as a result of xenogamy (genetic admixture) led to both the intrusion of offspring’s personal genome with hete- rozygous information and to the formation in the off- spring’s body of coexisting cell clones with opposite relation to the regulators of their growth and with their own deviant genetic programs of ontogenesis. 4) The emergence of cancerous clone and the discrete dispersion of its micro-populations around the body are performed before postnatal ontogeny in the manner used to dispose other embryonic tissues and organs. Thus the lymphatic system of individual adaptive immunity does not recognize the deposited cancer cells as foreign and does not destroy them. After the end of their disposition the subpopulations exist at their stable places like cell masses of smallest but different sizes being provided with life supporting stuffs by intruded host. 5) At a relevant time of a breadwinner’s life (mainly after 40 years of its age), the clone gets specific im- pulse to awake probably either from its specific pro- gram of ontogenesis or from relevant physiological or ecological carcinogens. Its subpopulations begin to rep- licate uncontrollably and comes into sight in the form of detectable extra cells masses of cancerous tissue, the malignant tumors. The initially largest one of subpopula- tions achieves detectable tumorous size far earlier in comparison to the initially smallest one. The first ap- peared cell mass is called the “primary” tumor. 6) The growth of all subpopulations of a cancerous clone is under control performed by their own united physiological mechanism which maintains the whole structure of cancer within its genetically predetermined size. The destruction of one or more tumors gives boost to growth of other sub-populations of the clone. 7) None carcinogenic mutations could be widely dis- seminated in the humankind because their rarity, ran- domness, and to the counteraction of natural selection. The currently observed increasing incidence of the dis- ease depends on the intensity of xenogamous genetic admixture within ethnically mixed populations. The study has been performed by exposure and analy- sis of various epidemiological, clinical, immunological, genetic, and experimental data concerning principal characteristics common for both cancer and other kinds of diseases, especially of hormonal ones. This approach allowed expose and highlight new ways toward the dis- covery of molecular level of immunogenic and genetic factors involved in the appearance, evolution, spreading, and maintenance of cancer. At least four decisive factors are involved in the crea- tion of malignancy: 1) Natural selection for hereditary immunity against life-threatening molecular ecological agents; 2) Ethnic diversification of humankind; 3) In- ter-ethnic crossbreeding; and 4) Globalization of hu- mankind. Points 1 to 3 predestined the origin of the dis- ease, whereas point 4 formed prerequisites and propel- ling forces for its pandemic spread. The revealed set of evidences allows for the demand
S. N. Rumyantsev / Open Journal of Immunology 1 (2011) 27-40 Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/ 38 that the origin of cancer is based on xenogamous intru- sion into individual genomes of relative but structurally foreign components able to control the development of cell clones constitutionally immune to physiological regulators prevalent at the intruded body. Like any other disease, cancer is characteristic of diversity in the course, manifestations, and severity of specific affections, as well as their sizes and stochastic focal disposition around the body. Individual differences in the manifestations and severity of discussed disease are associated with the phenomenon of stochastic focal distribution of cancerous zones around a body. The differences are of genetic ori- gin. This phenomenon is analogous to those characteris- tics of any other kind of pathology, being explained by the hybridization of persons possessing different grades of genetic predisposition to relevant pathogens. The methodological approach used in the performed study allowed present the first genetic explanation for the epidemic increase in cancer incidence. Like any other hormonal disturbance, cancer arises as a result of constitutional incongruence between relevant hormonal regulators and their receptors. The cancerous molecular make-up could arise and spread among the worldwide population because of xenogamy―crossbreeding among mutually distinct parents. From this point of view, the life-threatening disease could be considered as a rec- koning, both for the life-saving evolution of beneficial genetic immunity to relevant ecological agents and for the production of offspring unlike their parents. The integrative view of the origin of cancer and its spread around the world supplies a framework for un- derstanding the genetic nature of cancer pandemic and its rising incidence in the current worldwide population. The new paradigm allows a new explanation of the ori- gin of cancer and its pandemics as well as to launch a more complete discovery of inherited either suscepti- bility or immunity to cancer, for instance, by the deci- phering of phenetic functions of the genome’s region of 8q24 responsible for prostate cancer in Americans men of African origin as well as molecular make-up of the immunity of cancerous cells to relevant regulatory sys- tems, with potential applications for prevention and treatment. It also forces to reconsider the perspective of future investigations and to reassess the principles for cancer prevention and healing. 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