"Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future
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irk-123456789-1387072018-06-20T03:07:23Z "Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future Osinsky, S.P. Kelleher, D.K. Chekhun, V.F. Special topic 2012 Article "Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future / S.P. Osinsky, D.K. Kelleher, V.F. Chekhun // Experimental Oncology. — 2012. — Т. 34, № 2. — С. 70-74. — Бібліогр.: 44 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/138707 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Special topic Special topic Osinsky, S.P. Kelleher, D.K. Chekhun, V.F. "Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future Experimental Oncology |
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Osinsky, S.P. |
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"Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future |
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"Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future |
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"Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future |
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"tumor and host" by r.e. kavetsky (1962): implications for the past, present and future |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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"Tumor and host" by R.E. Kavetsky (1962): implications for the past, present and future / S.P. Osinsky, D.K. Kelleher, V.F. Chekhun // Experimental Oncology. — 2012. — Т. 34, № 2. — С. 70-74. — Бібліогр.: 44 назв. — англ. |
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Experimental Oncology |
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70 Experimental Oncology 34, 70–74, 2012 (June)
“TUMOR AND HOST” BY R.E. KAVETSKY (1962): IMPLICATIONS
FOR THE PAST, PRESENT AND FUTURE
S.P. Osinsky1*, D.K. Kelleher2, V.F. Chekhun1
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy
of Sciences of Ukraine, Kiev, Ukraine
2Institute of Functional and Clinical Anatomy, University Medical Center, Mainz, Germany
This paper aims to present a short history of the
concept of the development of tumor-host interaction.
The numerous facets of this concept started to be dis-
cussed in detail quite a long time ago, but especially
over the last decades and even more so over recent
years. This topic has received new impetus due to a re-
assessment by scientists of the biological nature
of tumor growth as well as the appearance of metho-
dological technologies that have allowed the clarifica-
tion of many older findings and the discovery of new
mechanisms. Especial attention has been devoted
to these issues by pathophysiologists from Germany,
Russia and Ukraine who have studied general patho-
logy and, in particular, oncology. The fruitful develop-
ment of Thiersch’s idea has been implemented in the
works of А. Bogomolets and, especially, by his fol-
lower R. Kavetsky who made a significant contribution
to the formation of the tumor-host concept.
The 50th anniversary of R. Kavetsky’s monograph
“Tumor and Host” (Kiev, Gosmedizdat, 1962) which
was perhaps the first main summary of data on this
subject is being celebrated in 2012. It is worth noting
that the special session “Tumor and Host Interrelation-
ships” held within the framework of the VIIIth Interna-
tional Cancer Congress which was held in 1962 in Mos-
cow was organized as a result of Kavetsky’s initiative.
The plenary lecture given by Kavetsky, together with
presentations by other scientists and active discus-
sions, provided a special impulse for new investiga-
tions in this field. As part of the celebration of these
two relevant scientific events, an attempt will be made
here to familiarize the readers with a short history of the
tumor-host problem while also presenting some recent
publications that have focused on the background
established more than hundred years by prominent
pathophysiologists of our time.
HISTORICAL PERSPECTIVES
At present it is hard to imagine that at the end
of the 19th and the beginning of the 20th centuries the
ideas on the autonomy of tumor growth were shared
by a number of leading pathologists, among whom Vir-
chow predominated. However, as far back as in 1861,
the Russian pathologist Pelikan pointed out that
Virchow’s concept was erroneous and declared that
a tumor is host-dependent and cannot be autonomous
in its growth (cited from Ruchkovsky, 1953 [1]). In the
quest for the truth, it is of interest to recollect that one
of the known misleading theories, namely that all tu-
mors, including carcinomas — i.e. tumors of epithelial
origin — are derived from connective tissue, in fact
belongs to Virchow [2]. Virchow’s claim has been
opposed and disproved by Cornil, Thiersch and von
Waldeyer. It was shown that in the case of epithelial
tumors, cells originate from the existing epithelium.
The studies of von Waldeyer showed that in their very
various locations, cancers are, in their origin, con-
nected with epithelial structures (cited from Coats
and Sutherland [3]). But in the above-mentioned
studies, an explanation of the mechanisms of tumor
cell invasion, in particular for cells of epithelial origin
into adjacent tissues, was absent.
Cohnheim, and in part, Ribbert, suggested that the
invasion of epithelial tumor cells is only possible when
an alteration of the connective tissue primarily occurs.
On the basis of this assumption, the concept that the
neoplastic growth is determined by tumor stroma was
formulated. Coats and Sutherland [3] have presented
the data concerning Thierschґs point of view on the
cause of cancer, taking into account the differences
between benign and malignant tumors. In the case
of benign tumors, normal tissues are able to prevent
tumor penetration into surrounding tissues, but in the
case of malignant tumors, adjacent normal tissues
become unable to form a barrier against tumor expan-
sion. In 1902, Borst summed up the discussion and
put forward a hypothesis concerning the relationship
between tumor and stroma [2].
It is possible to imagine that Virchow’s postu-
late partially originated from his own observations
concerning the stromal, i.e. the connective tissue
component, of neoplasia. In 1863, Virchow was
the first to identify leukocytes in the center as well
as in the periphery of tumor foci, ascertaining that
the inflammation is one of the predisposing factors
of tumor development [4]. It should be emphasized
that Cohnheim, who has been recognized as a pioneer
of the theory of inflammation, wrote: “There is no in-
flammation without the involvement of blood vessels”
[4]. Cohnheim explained the presence of leukocytes
in tumor tissue (characteristic of any inflammatory
focus) to occur through the migration of polymor-
phonuclear leukocytes from blood vessels supplying
the tumor. In total, all of the mentioned works have
Received: May 20, 2012.
*Correspondence: E-mail: osion@onconet.kiev.ua
Exp Oncol 2012
34, 2, 70–74
SPECIAL TOPIC
Experimental Oncology 34, 70–74, 2012 (June) 71
completely overthrown Virchow’s notion which was
dominating at that time [5].
An assumption concerning the destructive impact
of a tumor on its host, leading to anemia and general
weakness and sometimes even to serious constitutio-
nal consequences was made by Coats and Sutherland
[3]. The authors used terms such as dyscrasia and
diathesis to designate the state of a body predisposed
to the initiation and formation of a malignant tumor.
Nevertheless, direct evidence for such a predisposi-
tion was not available at that time. As early as 1865,
Thiersch for the first time declared the idea of the role
of connective tissue in cancer pathogenesis, taking
into account the ability of the connective tissue to op-
pose the invasion of epithelium (cited from Kavetsky
[6]). Developing this idea further, Bogomolets pro-
posed the concept of the physiological system of con-
nective tissue. According to his concept, connective
tissue is of utmost importance in the development
of many pathological processes including malignant
growth. Bogomolets noted: “Cancer can hardly arise
in a body displaying sufficient resistance of the reticu-
lo-endothelial system”. In this respect, he introduced
the term of “cancer diathesis, i.e. the predisposition
of an organism to cancer development” which was
in line with the preceding assumptions of Coats and
Sutherland. Working actively on this problem, Bogo-
molets arrived at a negation of tumor autonomy, in the
sense of tumor cells being independent of the host,
whereby he recognized that metabolic disturbances
and the reaction of the body are of utmost importance
for the origin and development of pathological pro-
cesses [7]. It should be emphasized here that he ad-
dressed the problems of the etiology and pathogenesis
of malignant growth from the point of view that the
organism should be considered as being one unity and
can itself be recognized as forming one unit with its
external environment. At the same time, he supported
the idea that metabolic disturbances and the reaction
of the organism are very important in the genesis and
development of pathological processes.
In Bogomolets’s text-book “Pathological Physio-
logy” (1923), the chapter on tumors contained sub-
chapters devoted to local and more general effects
of tumors on their host and the reaction of the host
to tumor development [8]. It is important to note that
Bogomolets, when considering connective tissue
as a physiological system, suggested that the internal
milieu of the organism, with its cellular and non-cellular
components possesses not only plastic but also tro-
phic and protective functions (cited from Nejman [9]).
At the same time, Bogomolets considered cancer
as not being able to develop in a host in which the
connective tissue exhibits normal resistance proper-
ties [10]. The same idea was almost simultaneously
declared by a number of French scientists (cited from
Bogomolets [10]). At that time, much attention had
been given to the study of connective tissue. The
active connective tissue, or in the words of Maximov,
the “mesenchymal reserve” (comprising histiocytes,
reticulocytes, endothelial cells and hematopoietic
elements and their derivates, namely leukocytes and
monocytes, and Hortega cells in the brain) was consi-
dered to be the most powerful system in the organism
under either physiological or pathological conditions
[11]. As early as 1909, Ulezko-Stroganova formulated
a thesis dealing with the significance of connective
tissue and its customary role in the initiation and deve-
lopment of malignant tumors, explaining the possible
causes of spontaneous recoveries from cancer [12].
At present, the cellular and non-cellular components
referred to above do in fact mirror the current concept
of the tumor microenvironment, or more specifically,
the molecular-cellular microenvironment of tumor
cells [13–21].
Bogomolets’ ideas on the active mesenchyma be-
ing a factor involved in restraining tumor growth were
fruitfully further developed by his follower Kavetsky, the
founder of the Ukrainian School of Oncology. In 1937,
Kavetsky proposed that: “Two interconnected pro-
cesses comprise the basis of carcinogenesis: (a) the
local process of carcinogenesis that later develops into
the real malignant tumor, growing by infiltration, and
(b) general changes in the body predisposing the pos-
sibility of the primary node being transformed into the
genuine tumor, with its further dissemination by means
of metastasis” [6]. This statement comprises the unity
of processes of malignant transformation of normal
cells as well as the development of the general disposi-
tion of the organism to tumor growth initiation, “which
in conjunction promote the development of malignant
neoplasia in the organism”.
Similar issues were raised by Greenstein
in 1941 when he contended that “tumor-host interac-
tion is the key to the problem of cancer” (cited from
Begg [22]). In Begg’s publications from the 1950s,
many questions concerning tumor-host interac-
tion were discussed. While some of them could not
be confirmed later, the principal statements still hold
true at present [22]. According to Begg, the concept
of “tumor-host interaction” referred to alterations trig-
gered by the tumor in metastasis-free remote tissues
of the host. In fact, in normal tissues of tumor-bearing
hosts, some alterations were evident, depending
on the stage of disease. Initially, such findings con-
cerned several enzymatic systems of the liver and
spleen. An important observation was that, as a rule,
tumors contain more nitrogen than that accumulated
in the tumor-bearing organism, due to a redistribution
of nitrogen in favor of the tumor and at the expense
of the host tissues, in particular muscle tissue. Mish-
chenko was apparently the first to carry out careful
investigations of nitrogen metabolism in animals with
experimental tumors as well as in cancer patients
at different stages of the disease [7]. Tumors utilize
both exogenous and endogenous substances in order
to meet their own synthetic requirements. Later, Mider
et al. in 1948 concluded that the tumor-bearing host
is in the peculiar state of negative nitrogen balance
and thus designated the tumor as a “trap of nitrogen”
72 Experimental Oncology 34, 70–74, 2012 (June)
with nitrogen only being lost to the urine (cited from
Kavetsky [7]).
The pronounced ability of tumors to utilize glucose
for amino acid synthesis was also discovered. Based
on the observations of Carrie and Ham (1949), sug-
gesting that tumor growth is accompanied by a de-
creased blood glucose concentration, Begg [22] pro-
posed that malignant tumors must be capable of ex-
tracting glucose from the blood. This idea was further
developed by Shapot [23, 24] who characterized the
tumor as being a “trap of glucose”. The biochemical
changes in the tumor-bearing organism were also
observed to be accompanied by disturbances in the
endocrine system, in particular the activation of the
pituitary-adrenal axis.
In the 1950s and 60s, Kavetsky and his collabora-
tors distinctly outlined the concept of “tumor-host
interaction”. Having summarized vast amounts
of experimental and clinical data, Kavetsky [7] stated
that at first, tumor growth as such is a host reaction
to a variety of physical, chemical and biological fac-
tors of the environment. In this respect, it is possible
to accept the definition of the tumor as a “dystrophic
proliferative reaction of the body to various harmful in-
trinsic and external factors that fundamentally disturb
the composition and structure of the tissues and cells
and alter their metabolism” as formulated by Petrov
[25]. Secondly, an autonomy or independence of tu-
mor growth is out of the question due to the mutual
relationships between the neoplasm and the host from
an early stage of tumor formation. At the VIIIth Inter-
national Cancer Congress, Kavetsky summarized the
principal issues of “tumor-host relationships”, which
were accepted by almost all oncologists [26, 27]. The
importance of the above-mentioned problem was con-
firmed by the number of monographs published in the
following years in which data on the mechanisms and
different aspects of the tumor-host interaction were
documented [28–30]. Two scientific conferences,
entitled “Tumor and Host” and “Tumor and Host Re-
lationship” were held in 1974 and 1980, respectively,
by the R.E. Kavetsky Institute of Experimental Pa-
thology, Oncology and Radiobiology (IEPOR) of the
National Academy of Sciences of Ukraine [31, 32].
Two decades later, the rising interest in tumor-host
relationships on a more up-to-date metho dological
level was marked by Kerbel’s article published
in 1995 in the special issue of Cancer and Metastasis
Reviews [33]. This review highlighted the role of the
organ and tissue microenvironment in the behavior
of solid tumors. The scope of the subjects covered was
very broad and included the biology of intratumoral
stromal fibroblasts, desmoplastic reactions observed
in invasive carcinomas, and the ability of stromal cells
to secrete different matrix metalloproteinases which
may contribute to metastatic processes. The author
pointed out that it is important to take tumor-host in-
teractions into account in almost every aspect of tumor
biology, especially metastasis.
The molecular aspects of tumor-host interaction
are now the focus of intense research. Liotta and Kohn
[14] considered the malignant tumor to be a “product”
of pathological misbalance in the tissue-cell assembly.
Here, the malignancy may be characterized as a state
formed in the setting of specific tumor-host relation-
ships at the molecular and cellular microenvironment
levels when the “host” participates in the induction,
selection and expansion of neoplastic cells, and in turn
receives potent impacts generated by the developing
tumor. From the human viewpoint, the behavior of tu-
mor cells seems to be driven by “their intention not
to become outcast”. For this reason, they synthesize
and secrete a variety of stimulating growth factors and
cytokines, which recruit stromal and other elements
into the tumor in order to provide the living environment
appropriate for tumor cells.
In turn, the locally activated “host” microenviron-
ment (cellular and non-cellular components) modifies
the proliferative and invasive behavior of tumor cells
resulting generally in an increased aggressiveness
of the primary tumor and malignant tumor progres-
sion. Zigrino et al. [34] indicated the significant role
of the interaction of tumor cells with stromal elements
during tumor progression, focusing on the ability
of tumor cells to modify the stroma, to change the
adjacent connective tissue and to modulate the cel-
lular metabolism of the “host”. In this way, stroma
will be formed which is “most comfortable” for the
realization of the tumor cell’s aggressive potential.
The main vital principle of “tumor cell life” may thus
be characterized as an intention to achieve optimiza-
tion and preservation of the metabolism even at the
expense of the “host” resources.
The immunological, metabolic, and hormonal
mechanisms mediated by the nervous system are
considered as being the “classical” mechanisms
of tumor-host interaction [35]. It is worth mentioning
that all of them are very closely connected and that
their molecular “crosstalk” forms the pathological
state referred to as tumor disease. Here, the metabolic
alterations will be briefly discussed to demonstrate
their impact on immune reactions of the host that are
of high importance in maintaining tumor-host interac-
tions. As far as a tumor-host relationship involving the
nervous system is concerned, it should be noted that
such studies have been considered as being obso-
lete for a number of different reasons. Nevertheless,
these questions have again been recently brought
into focus [36].
Pyter et al. [37] verified the hypothesis concern-
ing the ability of the tumor to induce a depression-
like state and to “switch on” the production of both
peripheral and central anti-inflammatory cytokines.
Authors have observed increased signs of depressive
and anxious behavior in rats with induced mammary
cancer in comparison to that seen in control animals.
Tumors have been found to produce significantly
more IL-1β than normal mammary tissue. The levels
of the inflammatory mediators IL-1β, IL-6 and TNF-α,
Experimental Oncology 34, 70–74, 2012 (June) 73
which provoke behavior similar to depression, as well
as the anti-inflammatory mediator IL-10 are seen
to be increased in the hippocampus of rats with mam-
mary carcinoma as compared to control animals.
In tumor-bearing rats, the level of circulating corti-
costerone inhibiting cytokine signals decreased while
the expression of genes coding the glucocorticoid
receptors in the hippocampus increased. The data
obtained clearly show that tumors are potent induc-
ers of shifts in emotional behavior. The suppression
of glucocorticoid-related reactions to stress may
exaggerate the negative effects of tumor-produced
cytokines in the context of the psycho-emotional
state of tumor-bearing animals. Based on the data
concerning tumor cell production of anti-inflammatory
cytokines capable of inducing depressive behavior
(anhedonia, anorexia, lethargy), a direct impact of the
“peripheral” tumor on the hypothalamo-hypophysis-
adrenal axis has been inferred.
Different physiological-biochemical reactions that
promote the vitality of tumoral as well as normal cells
form the basis of the metabolic mechanisms of tumor-
host interaction. This aspect of the tumor’s relation-
ship with the host is based on the microenvironment
of tumor cells which, as it is clear from numerous
investigations, is the dominant factor in the “tumor-
host” dialogue.
RECENT ACTIVITY
The current problems of tumor-host interactions
were the subject of the international conference
entitled “Tumor and Host: Novel Aspects of the Old
Problem”, that was held on September 21st–24th,
2010 in Kiev, Ukraine. The meeting was hosted
by the R.E. Kavetsky ІEPOR and was dedicated to the
50th Anniversary of the IEPOR. Plenary lectures, pre-
sentations and the general discussion emphasized the
impact of different aspects of tumor and host interac-
tions and their influence on tumor aggressiveness and
cancer progression, focusing in particular on immu-
nological aspects of tumor growth, the microenviron-
ment of tumor cells, signaling pathways mediating
the formation of the biological profile of tumors, and
new trends in cancer prevention, diagnostics and
therapy. The issues covered at this conference were
published together with a meeting report [38, 39].
A further noteworthy scientific conference entitled
“Tumor-Host Interaction and Angiogenesis: Mecha-
nisms and Therapeutic Implication” was also held this
year in Switzerland [40].
It is very important to underline that at present, the
interactions between tumor and host mainly concern
the interactions between tumor cells and stromal cells
as well as immune cells and bone marrow-derived cells
that were recruited into the tumor node. It somewhat
narrows the classic concept of the tumor-host relation-
ship which includes the different organs and systems
of the body and considers both systemic reactions
of the organism in addition to responses of stromal
elements to the tumor.
McAllister and Weinberg [41], while summarizing
the recent advances in tumor-host relationships de-
clared that many aspects of tumor biology can only
be explained by a detailed understanding of both local
and systemic interactions.
One of the manifestations of the systemic interrela-
tionships between the tumor and host can be consid-
ered to be the well-known recruiting of normal cells into
the tumor by signals from tumor cells that support the
survival of the neoplasia. It allows a characterization
of “the сancer as an ecosystem composed of tumor
cells and of non tumor cells residing in the tumor mi-
croenvironment or recruited to this site” [42]. It was
recently emphasized that “the original concept that
cancer cells do not manifest the disease alone, but
rather conscript and corrupt resident and recruited
normal cell types to serve as contributing members
to the outlaw society of cells” [43].
In this aspect, the statement of Goodwin et al. [44]
that “there is growing evidence that it is necessary
to go beyond the cell into the whole organism to fully
understand the biology of cancer and its treatment”
is very important and highly relevant. It has to be not-
ed that a personalized therapy needs to be rooted
in a consideration of the reality that any tumor growth
and progress involves a close interconnection with the
individual organism, and that the problem of an indi-
vidual patient’s management may only be successfully
achieved within the frame of the concept of “tumor-
host interaction”.
ACKNOWLEDGMENT
We thank the Publishing House “Akademperiodyka”
(Kiev) for the permission to publish the “Historical
perspectives” that is a part of chapter “Tumor-host in-
teractions and metabolic microenvironment of cancer
cells” by S. Osinsky, D. Kelleher, in: Osinsky S, Friess
H, Vaupel P. (eds.) Tumor hypoxia in the clinical setting.
Akademperiodyka, Kiev, 2011: 129–153.
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