Download interaction between tumor and immune system: the role of tumor cell

Experimental Oncology 32, 159–166, 2010 (September)
Exp Oncol 2010
32, 3, 159–166
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INTERACTION BETWEEN TUMOR AND IMMUNE SYSTEM:
THE ROLE OF TUMOR CELL BIOLOGY
N.M. Berezhnaya*
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of
Sciences of Ukraine, Vasylkivska, 45, Kiev 03022, Ukraine
In present work the role of tumor cell biology upon different conditions of their interaction with the cells of immune system is
discussed. The presented data show that it tumor cell biology that in many cases determines tumor antigen recognition and realization of cytotoxic action of killer cells. Here also we discuss own data obtained with the use of experimental tumor models (transplantable MC-rhabdomyosarcoma, B16 melanoma) and human tumors (soft tissue sarcoma, melanoma, breast cancer, ovarian
cancer, cervical cancer). It was demonstrated that various tumors have different sensitivity to antitumor action of activated (LAK)
and non-activated lymphocytes. Recent studies on the role of tumor cells in expansion and activity of different suppressor cells
(MDSC, Treg, Th17, M-2 macrophages, etc.) are overviewed. The role of organ-specificity and interaction of the components of
microenvironment (cells of immune system and stroma, tumor cells, endothelial cells, extracellular matrix) are discussed in details.
Along with the presentation of modern views on some patterns that characterize the development of drug resistance of different
tumors and capabilities of immune system cells to participate in lysis of resistant tumor cells, the authors present their own data
illustrating that resistant tumor cells reveal increased sensitivity to LAK. An analysis of the involvement of a number of molecules,
lymphocytes, and tumor cells in the phenomenon of elevated sensitivity to LAK action allowed to conclude that tumor cells reveal
high sensitivity at the background of decreased E-cadherin expression and increased CD40 expression.
Key Words: tumor cell biology, recognition, immunosuppression, resistance, LAK, E-cadherin, CD40.
At the end of 90th, a significant number of data
have been accumulated and have created an important field in oncology — tumor cell biology. This area
of research allowed to widen the knowledge about the
complex interactions between tumor and organism.
The role of biological patterns of tumor cells is especially prominent upon their interaction with the cells of
immune system. At present time it is considered that
the result of interaction between immune system cells
and tumor cells is equally dependent on the functional
state of immune system cells, and on biological patterns of tumor cells.
If one analyze different aspects of such interaction,
it becomes clear that biological properties of tumor are
reflected in: 1) recognition of tumor antigens; 2) character of immunologic response (growth inhibition or
stimulation, tolerance); 3) expression of antitumor
action of killer cells; 4) formation of immunosuppression; 5) influence of tumor cell patterns on formation
of microenvironment; 6) development of resistance
Received: July 13, 2010.
*Correspondence: E-mail: berezh@onconet.kiev.ua
Abbrevitations used: ABC — antigen binding cassette; BCRP —
breast cancer resistance protein; GM-CSF — granulocyte- macrophage colony-stimulating factor; HGF — hepatocyte growth factor;
HIF — hypoxia inducible factor; iNOS — inducible nitric oxide synthase; LMP — large multifunctional protein; LRP — lung resistancerelated protein; M-CSF — macrophage colony-stimulating factor;
MDR — multidrug resistance receptor; MDSC — myeloid-derived
suppressor cells; MICs — MHC class I related molecules; MMP —
matrix metalloproteinase; NO — nitric oxide; PAR — protease activated receptor; PDGF — platelet-derived growth factor; PGE-2 —
prostaglandin E-2; PSF — peptide supply factor; ROS — reactive
oxygen species; SCF — stem cell factor; TAP — transporter antigen
protein; UL-16 — human CMV glycoprotein; ULBPs — UL-16-binding proteins; VEGF — vascular endothelial growth factor.
to killer cell action and drug resistance; 7) efficacy
of immunotherapy etc.
Understanding the role of tumor cell biology for its
interaction with the cells of antitumor defense allows to
approach to the answers on numerous principal questions concerning fundamental aspects of tumor immunology and clinical immunotherapy, namely: 1) Why
tumor cells escape from immunological control?
2) Why there is no immunological response without
visible disturbance in immune system cells (in particular antigen-recognizing and killer cells)? 3) How can
tumor cell suppress immunological response? 4) What
is the role of tumor in activation of cells with suppressor activity? 5) How biological patterns of tumor
cell are reflected in formation of microenvironment?
6) Why immunotherapy is presently low-effective? etc.
RECOGNITION OF TUMOR ANTIGENS
It is well known that recognition of antigens, in particular, tumor ones, is a complex integral multifactor
process that depends on expression and functional
state of numerous surface and intracellular structures
of tumor cells and lymphocytes. This is related, firstly,
to expression by tumor cells of adhesive molecules,
I and II classes MHC antigens, expression and functional activity of transport proteins (ТАР-1, ТАР-2), and
also PSF1, PSF2-peptide supply factors, LMP (large
multifunctional protease) and its subunits — LMP-1,
LMP-2A, LMP-2B, LMP-7, LMP-10, 2-microglobulin,
MECL-1, PA-28, PA-28 proteins, taposin etc.
One could present many examples of the role of tumor cell biological patterns for an efficacy of antigen
recognition and processing. Among these, the characteristics of proteins involved in presentation process
should be mentioned. If taking into consideration just
ТАР and LMP, it’s evident that the rate of abnormal
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expression of these proteins is different in different
types of tumors. Defective ТАР expression is the mostly
frequent in melanoma (that’s why MHC I class antigen
expression is practically absent in melanoma cells)
and renal cancer. In contrary, in lung cancer cells and
intestinal cancer TAP expression is practically unaltered,
while in snasopharyngeal cell lines decreased ТАР expression doesn’t lead to altered HLA-A2 expression [1].
Altered presentation process may be related also
to the changes of expression of differentLMP proteins — LMP-1, LMP-2, LMP-7, LMP-10 etc. that occupy the central place in antigen presentation process
on antigen-presenting cells as well as on tumor cells.
As a rule, the decreased activity of these proteins is
observed, and such decrease is interrelated with tumor
cell patterns: for example, gangliosides produced
by prostate cancer cells decrease LMP-10 expression in dendritic cells thus altering presentation process [2]. In some cases, in particular in esophageal
cancer, combined change of expression of proteins
involved in presentation (simultaneous decrease
of LMP-2 and ТАР-1 expression levels) could be registered [3]. Presently it is evident that recognition process is extremely important and should be considered
and controlled during cancer immunotherapy as the
first stage of interaction between tumor and immune
system. Knowledge on tumor cell patterns is required
for prognosis of immunologic response on therapy due
to the possibility of its opposite action.
SENSITIVITY TO THE ACTION OF KILLER
CELLS
The main criterion of recognition effectiveness and
respectively of antitumor action of killer cells is the damage of target cells. The degree of tumor cell sensitivity
to the action of killer cells differs in tumors of various
histogenesis, localization and the stage of tumor progression, as well between the cells of the same tumor.
Along with this, different sensitivity exists as well toward
special populations of killer cells — CTL, NK, NKT, macrophages, neutrophils, etc. In some cases the maximal
antitumor effect is achieved upon the action of CTL,
in some cases — of NK and NKT, in some cases there
is a prevalence of neutrophil activity (especially at early
stages of tumor process), sometimes — an efficacy is
achieved upon combined action of different cells, and
at last, killer cells, eosinophils or basophils may be involved, but their action is poorly studied yet [1].
Unfortunately, recognition not always results
in destruction of tumor cells. The degree of sensitivity
of tumors and cell clones from the same tumor could
differ and depends on a number of conditions. This is
evidenced by the results of studies of solid tumors,
among which melanoma is the most frequently studied
object. First of all, it is related to the sensitivity of cells
of primary and metastatic melanoma to cytotoxic action of CTL, NК, NKT etc. It is known that NK cytotoxicity
strongly depends on expression of different activatory
receptors, among which the most important are NКG2D,
NCR (NKp46, NKp30, NKp44), DNAМ-1 (co-stimulatory
Experimental Oncology 32, 159–166, 2010 (September)
molecule). The cells may differ by the expression levels
and density of these receptors [4–7]. However, the expression of these receptors, their surface density and
functional activity could not guarantee tumor cell lysis.
Necessary condition for lysis is the expression of receptors’ ligands by tumor cells. Ligands for NКG2D are MIC
(MICA, MICB) associated with nonclassic I class MHC,
and ULBPs (ULBP1, ULBP2, ULBP3, ULBP4) — the members of large protein family related to cytomegalovirus
UL16. The members of ULBP family may serve as the
ligands for NCR, while CD155 (poliovirus receptor PVR)
and N-ectin2 (CD112) are ligands for DNAМ. — From
two DNAМ-1 ligands CD155 is frequently expressed
in melanoma cells, while CD112 — rarely [4–7]. The
recent data have shown that DNAМ-1 plays a central
role in control of recognition of metastazing cells, and is
responsible for the response to immunotherapy with the
use of IL-2, IL-12 and IL-22 [5]. Such role of DNAМ-1 is
determined by its participation in realization of activating
signals received from tumor cells. The role of DNAМ1 and CD155 interaction for lysis of metastazing cells is
determined by the activation of perforin system.
Receptors of killer cells, for example, NK, often vary
by recognition of different ligands, while tumor cells
significantly vary by ligand expression [6, 7]. For example, high expression level of ligands to activatory receptors and low level of ligands to inhibitory receptors
is typical for cervical carcinoma cells [8]. Melanoma
cells are heterogeneous by MICА and ULBP2 expression even in metastases. Among soluble forms of
these ligands, MICА is detected much more rarely than
ULBP2. On the cells of different carcinoma the most
frequently MICА and ULBP1 are expressed; highly
differentiated tumors of invasive breast carcinoma are
characterized by high MICА expression [9, 10].
Variability of killer receptors on lymphocytes and their
ligands on tumor cells partially explain the different sensitivity of tumor cells to the action of killer cells, which is
supported by a numerous data. For example, the study
of different glioma cell lines that express ULBP2 and
ULBP3, or ULBP1 and ULBP4, has shown that in first case
the cells were highly sensitive to NK-mediated lysis, and
in the other — were low sensitive [11].
Apart from expression patterns of mentioned receptors and their ligands, the lysis may be hindered
by soluble forms of these ligands produced by tumor
cell — sULBP2 and sMICA, as well as soluble form
of sNКG2D receptor. At last, inhibitors of mentioned
ligands also may contribute to the disruption of tumor
cell lysis, in particular matrix metalloproteinases expressed by tumor cell [12].
Another important component of cell lytic process
is presented by adhesion molecules grouped in five
large families. In 1990 it was shown that cells highly
sensitive to CTL could be characterized by ICAMpositive phenotype. Presently it is known that ICAM-1
plays an important role in realization of cytotoxicity: the
study of cells of primary and metastatic melanoma has
revealed that primary melanoma cells express ICAM-1
and demonstrate an expressed sensitivity to CTL, while
Experimental Oncology 32, 159–166, 2010 (September)
cells of metastases with low sensitivity to CTL do not
express the molecule. In melanoma metastases inhibitor of granzym B has been found [13].
The cells of different tumors differ not only by the level
of ICAM-1 expression, but also by intracellular signals
induced via interaction of this molecule with its ligand.
Such interaction in breast cancer cells results in activation of transcription factor Fos related antigen-2 that is
accompanied by elevated invasion and metastasis [14],
while in melanoma analogous interaction leads to activation of NF-B with the involvement of TNF [15].
Along with intracellular ICAM-1 molecule and its
soluble form, also membrane-bound mICAM-1 has
been described. The role of mICAM-1 is yet poorly
understood but it has been shown that it may interact
with lymphocytes decreasing their adhesion capacity, and could be found only in portion of tumor cells.
Comparative study of mICAM-1 in prostate cancer
cells and breast cancer cells demonstrated that this
molecule was present in prostate cancer cells, but was
absent in breast cancer cells [16].
CD40 glycoprotein from TNF receptor family could
be ascribed to multifunctional molecules involved in
cytotoxicity process. CD40 molecule plays a central
role in cell proliferation, activity and survival [17]. An
interest to this molecule and its involvement in malignant
growth is based on a number of important facts. Many
solid tumors (melanoma, renal, bladder, breast cancers
etc) express CD40 receptor, some express CD40 ligand
(CD40L), and in some cases simultaneous expression
of CD40 and CD40L may be detected [17]. CD40/
CD40L-interaction may cause oppositely directed effects — tumor cell death and increased tumor growth
with involvement of different mechanisms. CD40 expression may be associated with drug resistance via
caspase-dependent or caspase-independent pathways
[17]. CD40 expansion and its activation is often accompanied by expression of co-stimulatory and adhesion
molecules, Fas-antigen etc.CD40 may interact with
myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) [18]. Nowadays it became possible
to explain ambiguousness of influence of CD40/CD40L
interaction of tumor growth. It has been shown that
low ligation level (as a rule, with involvement of soluble
CD40L) increases survival and proliferation, while high
ligation level (mCD40L) results in apoptosis. The mentioned studies were performed on bladder carcinoma
cells and allowed to conclude that the result of CD40/
CD40L interaction depends on the balance between the
signals inducing survival and apoptosis [19].
For characterization of tumor cell sensitivity of various human and animal tumors to antitumor action
of autologous lymphocytes, we have studied interaction
of tumor cells (soft tissue sarcoma, cervical cancer,
ovarian cancer, breast cancer, melanoma, models of
MC-rhabdomyosarcoma and В16 melanoma) with lymphocytes in diffusion chambers. Tumor cell sensitivity
has been studied toward activated and non-activated
lymphocytes. It has been shown that sensitivity of different tumors to the action of autologous non-activated
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lymphocytes varies. The most expressed antitumor
activity has been registered for lymphocytes of patients
with soft tissue sarcoma, and the lowest one — for lymphocytes of patients with cervical cancer. Melanoma
cells, ovarian and breast cancer cells revealed similar
sensitivity to the action of lymphocytes. We have noted
an expressed heterogeneity of sensitivity to the action
of autologous lymphocytes of tumor cells of common
genesis and histogenesis (skin melanoma, soft tissue
sarcoma). During the study of tumor growth dynamics
on different models it has been detected that at the
stage of tumor growth activation, lymphocytes of animals bearing MC-rhabdomyosarcoma inhibited tumor
growth, and with melanoma — stimulated it.
To find out with what molecules expressed in lymphocytes and tumor cells are involved in regulation
of antitumor activity, we have studied the epression
of CD25, ICAM-1, CD56, CD11b, CD71, CD40, p53,
and marker of proliferating cells IPO-38. As we have
shown, an expressed antitumor activity of lymphocytes
of patients with soft tissue sarcoma was associated
with ICAM-1 expression by tumor cells, and CD11b,
CD25 on lymphocytes. For melanoma, no statistically
significant results were obtained.
Differences in antitumor activity of LAK activated
by IL-2 were found to be more expressed in different
human tumors and animal models, in particular: 1) antitumor activity toward soft tissue tumor cells was even
higher; 2) activity of lymphocytes of cervical cancer
patients was sharply elevated; 3) activity toward ovarian and breast cancer cells was significantly elevated;
4) IL-2 activation neutralized stimulation of melanoma
growth and significantly potentiated an antitumor
action of LAK toward MC-rhabdomyosarcoma cells.
Oveall, different human and animal tumor cells demonstrated various sensitivity to the action of autologous
lymphocytes, activation of which in some cases drastically elevated their antitumor action, in some cases —
markedly increasedt, and in some cases — neutralized
the negative effect of non-activated lymphocytes.
Taking into account the role of CD40 expression
in tumor cells for antitumor activity of lymphocytes,
we have studied CD40 expression in breast cancer cells
(duct carcinoma and different benign tumors), and have
shown that benign and malignant breast tumor differed
by CD40 expression, which was significantly higher
in malignant tumor cells. It was found that an expressed
antitumor activity of peripheral blood lymphocytes was
in many cases associated with high expression level
of CD40 receptor by malignant tumor cells.
To prove the role of CD40 expression in tumor cells for
lymphocyte activity, we performed a study with blocking
of CD40 on tumor cells by recombinant CD40L protein.
It resulted in the significant decrease of the activity of
regional lymph node lymphocytes, and at much lower
degree — peripheral blood lymphocytes of the patients.
IMMUNOSUPPRESSION
One of the most important achievements of modern immunology is identification of the different types
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of cells with suppressor activity. The relation exists
between the expansion of various cell types with
suppressor activity and biological patterns of tumor
cells. It is grounded on the fact that tumor cells significantly differ by the level of production of various
substances — inducers of cells with suppressor activity. Inducers of cells with suppressor activity account
some tumor antigens, arginase-1, prostaglandins,
iNOS, NO, ROS, such cytokines as SCF, M-CSF,
GM-CSF, VEGF, IL-6, various chemokines and other
cytokines [20]. Presently few cell populations and
subpopulations with suppressor activity are identified:
MDSC, CD4+CD25+FOXP3+ (Тreg), CD69+CD4+CD25FOXP3-CD122+, suppressor CD8 T-lymphocytes that
express CD28, CD29, CD57, CD94 and at low level
different activation markers, macrophages-2 (М-2);
at certain conditions suppressor action can be caused
by Th17, mast cells, basophils, eosinophils, etc. [1].
The majority of mentioned populations and subpopulations of suppressor cells are heterogeneous and are
presented by different cell clones. Presently the most
studied suppressor cells are MDSC and Тreg that possess wide spectrum of immunosuppressive influence
toward NK, NKT, effector CD4- and CD8-lymphocytes,
maturation of dendritic cells, and also are able to promote inflammation, angiogenesis, damage of epithelial
barrier thus enhancing metastasis, etc. [20]. Inflammation creates a favorable background for expansion
of all suppressor cells, and many pro-inflammatory
cytokines promote their accumulation. Activity of suppressor cells becomes essentially expressed at the
conditions of tumor microenvironment, and the polarization of macrophages of microenvironment to М-2 illustrates such statement [21].
MDSC could be detected upon the development
of many human and animal tumors in peripheral blood,
spleen and area of tumor localization. There is a hypothesis that in humans MDSC of various localization
possess similar CD11b+CD33-CD34-CD14-HLA-DRphenotype [22]. At present time it has been estimated
that in some tumor cases other MDSC subtypes are
formed. In particular, in melanoma and hepatocarcinoma patients, CD14+ and HLA-DRlow subtype has
been found while in enteric carcinoma MDSC possess
characteristics similar to these of macrophages [22].
Intracranial administration of glioma cells of TL line to
rats resulted in formation of MDSC that express such
markers as His48 and CD11bc. These cells express
arginase-1, iNOS, TGF etc., but still NO is considered
as a primary mechanism of suppression [23].
Recently, in many tumors (liver and lung cancers,
melanoma) subpopulations of suppressors that do not
express CD25 and FOXP3 were identified. Their number increases along with tumor progression, and they
differ from other CD4+CD25+ suppressor cells by
expression of CD122 and membrane bound TGF1,
as well as an absence of IL-10 production [24].
Suppressor cells may reveal independent suppressor activity, or act synergistically as it has been shown
for MDSC and Treg. It is known that the development
Experimental Oncology 32, 159–166, 2010 (September)
of tolerance toward special tumor antigens (some
tumor cells differ by the content of such antigens)
creates a significant barrier for lysis by killer cells and
for efficacy of some types of immunotherapy. That’s
why it is of interest that the development of tolerance
is associated with accumulation of MDSC and Treg,
while the presence of MDSC favors to Treg generation.
Moreover, expression of CD40 by MDSC that further
interact with CD40L of Т-lymphocytes is required for
Treg accumulation [18]. These data revealed new
properties of MDSC and demonstrated that CD40/
CD40L blocking may serve as a therapeutic approach.
However, it should be considered that such blocking
may have negative consequences as well.
Different suppressor cells differ by an ability to react
on the action of various inducers of their expansion. For
example, MDSC express receptors to PGE-2 that is an
inducer of some suppressor cells. However, different tumors differ by production of this mediator. For example,
murine mammary gland carcinoma (4Т1) is characterized by high accumulation of PGE2 and MDSC in parallel
with accumulation of pro-inflammatory cytokine IL-1
[25]. In some tumors Fas/FasL-interaction may mediate
not pro-apoptotic functions, but promote the proliferation, and such fact has been noted in PGE2-dependent
3LL lung cancer. It has been shown that MDSC accumulation occurs with the involvement of PGE2, inflammation development, progression and tumor escape
from immunological control [26].
Similarly to other cells, for manifestation of suppressor activity of Th17-lymphocytes inflammation is favorable, too. These cells are accumulated
in melanoma, enteric cancer, and breast cancer [27].
At certain conditions Th17-lymphocytes may also
reveal synergistic action with other suppressors, for
example, Treg-lymphocytes. In many tumors a significant amount of infiltrating lymphocytes is represented
by Th17 in combination with increased IL-17 level. High
level of Th17 infiltration is observed in hepatocellular
carcinoma, while infiltration density by lymphocytes
correlates with blood vessel density and duration
of remission period [28]. Taking into account these
facts, the authors concluded that Th17-cell accumulation and increased IL-17 production may serve as a
prognostic criteria for hepatocellular carcinoma, and
Th17-lymphocytes — as a target for therapy [28].
Organ specificity affects manifestations of suppressor activity of Treg too, and this has been observed
in glioma and skin cancer [29, 30].
All mentioned above suppressor cells are characterized by unspecific influence on different effector cells. However, wide spectrum of their inhibiting
effects may be reflected also in inhibition of cells
involved in formation of antitumor immunity. First of all,
it is related to expansion of tumor-specific cytotoxic
T-lymphocytes. A possibility of different suppressor
cells induction and their activity level at large extent
depend on biological properties of tumor cells and
their organ specificity.
Experimental Oncology 32, 159–166, 2010 (September)
TUMOR MICROENVIRONMENT
Biological properties of tumor cells manifest itself
in tumor microenvironment, and the patterns of its
formation depends on the following main factors: 1) organ specificity differing between organs and tissues
(determines composition of stromal components and
vascularization); 2) functional activity of immune cells,
stroma; 3) extracellular matrix; 4) tumor cell patterns;
5) character of interaction between the components
of microenvironment; 6) complex system of regulation with involvement of different cytokines and other
biologically active molecules produced by all components of microenvironment [31]. Active interaction
between all components of tumor microenvironment
(fibroblasts, myofibrilles, endothelial cells and immune
system, extracellular matrix) and tumor cells occurs in
microenvironment of all solid tumors and determines
at large extent the phenotypic patterns of tumor cells,
their ability to metastasis, invasion, neovascularization
as well as the properties of other cellular components
of microenvironment (phenotype, cytokine secretion).
Metabolic and pathophysiologic patterns of microenvironment are also important. This field is also
actively studied, and presently many transcription
factors were described, which regulate different functions of cells in microenvironment, hypoxia and the
level of production of hypoxia induced factors (HIFs),
patterns of oxygen transport and metabolism of iron,
glycolysis, etc. [32]. However, it remains unclear what
is the relation between metabolism, pathomorphologic
patterns and components of microenvironment.
At present time the cells of stromal microenvironment, their interactions with tumor cells and immune
system are actively studied. The most popular object
of such studies are fibroblasts that at normal state restore homeostasis, but upon tumor development and
influence of different factors could differentiate into
myofibroblasts, express MMPs, participate in induction of immunosuppression, promote extracellular matrix remodeling and acquire new phenotypic patterns
[33]. There are no doubts that stromal cells are able to
affect tumors bipolarly, because they may participate
in tumor regression or promote tumor growth. The latest statement is supported by the data that melanoma
fibroblasts may suppress NK cytotoxicity, cytokine
production by these cells, and inhibit their activatory
receptors — NKp44, NKp30, DNAM-1 [34].
As it has been shown, fibroblasts may be involved in
activation of resting tumor cells, deposition of type I collagen (Col-I) and development of fibrosis in microenvironment of melanoma metastases that promote their
proliferation [35]. This is based on biochemical processes that lead to reorganization of cell cytoskeleton
with active participation of 1-integrin and Col-I. At the
microenvironment, favorable conditions for fibroblast
activation are generated because tumor cells produce
different soluble factors, in particular VEGF, TGF,
PDGF, HGF that locally activate fibroblasts modifying
their phenotype and functions. That has been observed
in breast cancer cell when co-cultivation of MDA-
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MB-23 cells and fibroblasts elevates aerobic glycolysis
that is used by tumor cells for its own growth [36].
Of interest is also the study of endothelial cells
that determines vascularization intensity, capillary
system, the state of vessel wall etc. — factors that at
large extent depend on organ specificity. Endothelial
cells of vessels actively participate in the interaction
with stromal tumor cells, immune system, extracellular
matrix, and this process is accompanied by secretion
of various biologically active compounds, in particular,
angiogenic factors. Developing hypoxia promotes
SDF-1 secretion by epithelial cells increasing their
adhesion to all cell types.
An influence of organ specificity on microenvironment patterns is reflected at the level of tumor stem
cell. For example, stem cells isolated from glioma by
many parameters do not differ from normal stem cells
of nervous tissue — the property typical for brain tumor
cells [37]. Glioma cells express molecules responsible
for their migration and invasion, in particular PAR-2 —
protease activated receptor-2 [38]. During glioblastoma
growth normal monocytes may differentiate to MDSClike phenotype. This has been detected during the study
of glioma cells from patients and in glioblastoma cell
lines cultured with normal monocytes. Such monocytes
produce IL-10, TGF, B7-H1, have decreased ability to
phagocytosis and elevate apoptosis of target cells [39].
Possibly, such phenomenon could be explained by the
patterns of local immunity of the brain.
The role of extracellular matrix is very important.
It is composed from different proteins – MMPs, lyzosomal enzymes, deoxyribonuclease, elastase, etc.
Dependent on conditions and organ specificity, protein
composition of extracellular matrix may be altered
because of active interaction of these proteins with all
cells of microenvironment [31, 40].
At the conditions of microenvironment, there could
be also alterations at genetic and epigenetic levels
found even between the cells of the same tumor. At the
background of genetic and epigenetic changes, metastatic potential of tumor cells is formed [29, 30]. Presently it is known that epigenetic changes are related
to altered expression of the enzyme that methylates
cysteine residues CpGs, and is involved in the development of malignant tumors [41].
So, microenvironment creates the conditions for
altered interaction between the cells of microenvironment and extracellular matrix. That’s why it is accepted
that invasion and metastasis are the results of altered
cell-to-cell interactions as well interactions between
separate cells and MMPs [14].
DRUG RESISTANCE
Among the most serious problems of modern oncology tumor drug resistance should be mentioned. This
problem has been studied in plenty of researches, many
molecular mechanisms have been revealed, and the role
of genetic and epigenetic disturbance has been shown
[42]. Drug resistance is determined by heterogeneous
mechanisms that in part are mediated by biological
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patterns of tumor cells. In particular, there are revealed
notable differences in expression of proteins involved
in the development of drug resistance. The majority of
such proteins are related to АВС family (ATP-binding
cassette), that includes MDR, P-gp, BCRP etc., but also
some proteins, for example, lung resistance-related
protein (LRP), that are not a members of this family.
Comparative evaluation of expression of mentioned
proteins by tumors evidences on their varied expression
levels in different tumors. For example, melanoma, pancreatic carcinoma, rhabdomyosarcoma etc., possess
high expression level of these proteins. However, some
tumors or tumor cell lines of similar genesis may vary by
expression rate of these proteins or their combinations.
For example, in neurosarcoma MRP-1 was expressed
in all primary tumors, P-gp and BCRP were expressed
much more rarely, while in rhabdomyosarcoma — MDRproteins were expressed in different combinations in
the majority of cases. These data allowed concluding
that parallel expression of different MDR-proteins may
be caused by simultaneous involvement of different
mechanisms of drug resistance formation that lead to
decreased survival [43].
It is of special interest that mentioned above proteins are not only drug resistance markers, but are
expressed also by many cells of immune system,
participate in regulation of immunologic response,
play role in differentiation, maturation and migration
of these cells, enhance antigen-recognizing potency
of dendritic cells [44]. Moreover, mentioned proteins
may be recognized by immune system cells. This allows explaining an elevated sensitivity of some breast
cancer cell lines to LAK action by P-gp expression [45].
The expression of tumor-associated antigens may
cause cell lysis of resistant tumors. Resistant cells of
Hodgkin’s lymphoma and primary tumors express
MAGE A4, SSX2, survivin, and NY-ESO-1, that are
recognized and lyzed by cytotoxic T lymphocytes [46].
There is one aspect of this question — upon the
influence of many anticancer drugs some resistant
tumors acquire elevated sensitivity to the action
of killer cells. This is supported by the data showing an
elevation of tumor sensitivity to NK-induced apoptosis,
and many other reports. However, the positive effect
of drugs on tumor cell sensitivity to NK action could be
associated with their resistance to the action of killers
from other population — cytotoxic T lymphocytes [47].
The studies performed by us with the use of cells
from different tumors (experimental and clinical observations), resistant to different drugs, have shown the
following. First, tumor cells (models of transplantable
MC-rhabdomyocarcoma and B16 melanoma), resistant to doxorubicin reveal elevated sensitivity to LAK
compared with sensitive tumor cells Second, elevated
sensitivity to LAK action has been revealed not only by
resistant tumors of animals, but also by resistant human tumors. Third, elevated sensitivity to LAK action
could be increased by pretreatment of resistant tumor
cells by low doses of drugs [48, 49]. Forth, upon study
of expression of Е-cadherin, CD40, IPO-38, р53, pan-
Experimental Oncology 32, 159–166, 2010 (September)
cytokeratin, CD54, CD11b, CD25, receptors of lectins
(soybean, coral bean, lentil) by resistant tumor cells and
lymphocytes () it has been shown that an expressed
antitumor action of LAK is associated with high expression levels of CD40, р53, IPO-38, and decreased
expression of Е-cadherin in tumor cells, and elevated
expression of CD25, CD54, receptors of soybean, and
unaltered CD40 expression in lymphocytes. Combination of pronounced sensitivity to LAK action with decreased Е-cadherin expression could be explained by
the fact that decreased Е-cadherin expression leads to
distorted signaling with involvement of some transcription factors (Wnt, PKD-1, Int-2 etc.), accumulation of
-catenin in nucleus, activation of transcription factors
NF-B, АP-1 and others, with the following proliferation
of tumor cells that makes them more sensitive to LAK
action and leads to lysis [50, 51].
So, concluding this part, it is worth mentioning
that the study of drug resistance has determined the
creation of new field of research — interplay between
immune system and drug resistant tumor cells.
IMMUNOTHERAPY
The presented facts allow concluding that an efficacy of different types of immunotherapy strictly
depends on tumor cell biology, and its failure — on
insufficient knowledge of these patterns in each particular case. However, this fact points on necessity
of further studies in this field creating the basis for
progress of oncoimmunology and development of
new immunotherapeutical approaches. Knowledge
on tumor cell biology explains why efficacy of immunotherapy is yet unsatisfactory: during tumor growth
its antigenic composition, phenotype, character of
interaction with stromal cells and immune system
change steadily, and different stages of tumor growth
are reflected in biological patterns of tumor cell. At all
stages of tumor growth tumor cell realizes its «strategy» — the term introduced by H. Salih. That’s why to
overcome these problems, it’s necessary to combine
all required knowledge with maximal individualization
of immunotherapeutical approaches.
CONCLUSION
Tumor cell biology includes numerous characteristics: antigenic composition and ability to induce
different forms of immunologic response, phenotype,
synthesis and production of cytokines and other biologically active compounds, ability to autocrine growth
regulation, tumorigenecity, induction of suppressor
cell expansion, invasiveness, metabolic potential, etc.
In reality in each particular case it iss a difficult and not
always feasible task to consider all mentioned above
characteristics as well as other possible ones. Along
with this it is evident that tumor cell ‘strategy’ realized
via its interrelation with the cells of immune system
could not be overcomed without considering special
biological patterns of tumor cells, especially their
ability to stimulate growth, induce the development of
tolerance, and activation of suppressor cells. It seems
to be true that immunotherapy should be based only at
Experimental Oncology 32, 159–166, 2010 (September)
mentioned fundamental approach, in particular, such
promising types of therapy as vaccination and adoptive
transfer of activated cells of immune system. Quick
development of modern oncoimmunology allows
believing that from complex parameters that reflect
biological patterns of tumor cells, the properties that
will guarantee the realization of any type of therapy will
be selected — to help but to do no harm.
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