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
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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
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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
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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
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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
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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-
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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 disposethe
lungs, bones, liver, and brain. Other places of a body are
seen far less accessible for secondary tumors. One ques-
tion arise immediatelyare 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.
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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-
0primary tumor at the age 74 years. 1-37secondary tumors at the age
82 years (1-31bone tumors; 32-34lung tumors; 35 and 36lymph
nodes tumors; 37soft 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 paradigmthe hypothesis of genome
intrusionabout 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 xenogamycrossbreeding 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. The design of families
with future cancer-free genealogy and the restriction of
xenogamy should get their place in the discussion
about perspective approaches and investigations for
cancer prevention. The impact of proposed alternative
hypotheses on the future outcome of cancer therapy is
expected first of all in the development of methods and
means for the suppression of genetic unresponsiveness
(hereditary immunity) of cancer cells to physiological
regulation of cell dividing.
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