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Macrophages in human cancer: Current and future
aspects
Michael R Mallmann, Susanne V Schmidt, Joachim L Schultze
Department of Obstetrics and Gynecology, Center for Integrated Oncology, University of Bonn, SigmundFreud-Str. 25, D-53105 Bonn, Germany; Genomics and Immunoregulation, LIMES-Institute, University of
Bonn, Carl-Troll-Str. 53, D-53115 Bonn, Germany (MRM), Genomics and Immunoregulation, LIMESInstitute, University of Bonn, Carl-Troll-Str. 53, D-53115 Bonn, Germany (SVS), Genomics and
Immunoregulation, LIMES-Institute, University of Bonn, Carl-Troll-Str. 53, D-53115 Bonn, Germany (JLS)
Published in Atlas Database: May 2012
Online updated version : http://AtlasGeneticsOncology.org/Deep/MacrophagesInCancerID20112.html
DOI: 10.4267/2042/48157
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
(Steidl et al., 2010; Lenz et al., 2008; Hammes et al.,
2007; Zhang et al., 2011c; Kamper et al., 2011) and
uveal melanoma (Bronkhorst et al., 2011). In contrast,
it has been linked with a favorable prognosis in
colorectal and gastric cancer (Forssell et al., 2007;
Sconocchia et al., 2011; Ohno et al., 2003).
Interestingly, several studies now confirm that the
location of TAMs in the tumor microenvironment and
in regard to tumor cells seems to influence their
prognostic role (Ohno et al., 2003; Allavena and
Mantovani, 2012). In colon cancer for example, higher
macrophage infiltration at the invasive front of the
tumor is associated with both an improvement of
overall survival and reduced hepatic metastasis (Zhou
et al., 2010).
The classical six hallmarks of cancer are cell growth,
ignoring growth-inhibition, the avoidance of cell death,
replication without limitation, sustained angiogenesis
and invasion through basement membranes into
circulation (Hanahan and Weinberg, 2000). Growing
knowledge on the biology of cancer stresses the role of
the immune system, in particular macrophages, on
several aspects of tumor biology. It more and more
becomes clear that beside the classical six hallmarks,
novel hallmarks of cancer can be assigned to cells of
the microenvironment. Tumor-associated macrophages
as part of the tumor microenvironment are involved in
novel hallmarks of cancer such as tumor-promoting
inflammation and avoidance of immune destruction.
Moreover, they are actively involved in all classical six
hallmarks by exerting TAM-specific tumor-sustaining
properties discussed below (Hanahan and Weinberg,
2000; Hanahan and Weinberg, 2011) .
Introduction
As cancer represents a very diverse biology depending
on the genetic background, the organ of origin and
confounding factors it remains ambitious to dissect this
complex cellular microenvironment into its main
driving factors. Among these factors an important role
has been attributed to both the adaptive and innate
immunity. For a long time, the immune regulatory
capacity (e.g. regulatory T cells) of the adaptive
immune system was a major focus of research
concerning the involvement of immune cells in the
tumor microenvironment with only few reports
published on its role in tumor growth promotion and
metastasis.
In contrast terms such as angiogenesis, tumor growth or
metastasis have been attributed to cells of innate
immune origin (Hicks et al., 2006). The innate immune
system is represented by different cell subsets including
natural killer (NK) cells, dendritic cells (DC),
neutrophils, and macrophages (MΦ). Tumor-associated
macrophages (TAMs) constitute a major part of the
leukocytic infiltrate in human cancer and the amount of
tumor infiltrating macrophages has early been
associated with clinical outcome (Mantovani et al.,
2008; Pollard, 2009). When assessing studies that
identified TAMs simply as CD68+ cells it is
challenging to assign a strict pro- or anti-tumorous
function to the TAM infiltrate. Nevertheless,
macrophage infiltration is associated with poor
prognosis in breast cancer (Finak et al., 2008; Beck et
al., 2009), Hodgkin's lymphoma (Steidl et al., 2010), Tcell lymphoma (Niino et al., 2010), cervical cancer
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Mallmann MR, et al.
molecularly
characterize
small
numbers
of
macrophages from human tumor specimens (Clark et
al., 2007).
Origin and activation status of
macrophages
Macrophages are in general believed to arise from
circulating monocytes that emigrate from blood vessels
and differentiate into macrophages in the peripheral
tissue. A variety of tissue associated macrophages exist
that exert an important role in tissue homeostasis.
Under homeostatic conditions, tissue macrophages
comprise langerhans cells in the epidermis, osteoclast's
in the bone, alveolar macrophages in the lung, red-pulp,
white-pulp,
marginal-zone
and
metallophilic
macrophages in the spleen, kupffer cells in the liver and
microglial cells in the central nervous system (Gordon
and Taylor, 2005). In general tissue macrophages are
believed to exhibit an intrinsic anti-inflammatory
phenotype under homeostatic conditions (Murray and
Wynn, 2011).
Macrophages are subject to a variety of concurrent
stimuli in vivo. In vitro, macrophages can be polarized
by single agent stimulation into rather pro- or antiinflammatory macrophages. According to the stimulus,
macrophages are divided into a simplified M1-like and
M2-like phenotype classification analogue to the Th1Th2 dichotomy in T cell biology (Biswas and
Mantovani, 2010). The pro-inflammatory "classically
activated" M1-like phenotype can be induced by
inflammatory signals such as interferon, LPS and other
bacterial stimuli and mediates defense against bacteria,
protozoa and viruses (Murray and Wynn, 2011). The
"alternatively activated" M2-like phenotype is induced
by IL4 or IL-13 ("M2a"), LPS or immune complexes
("M2b"), IL-10 ("M2c") and is associated with wound
healing and tissue repair (Gordon, 2003; Gordon and
Martinez, 2010). As there exist more stimuli than those
mentioned, consecutively a plethora of other
macrophage phenotypes have been described both in
vivo and in vitro. Whereas they often share some
features with M1-like or M2-like macrophages they
mostly exhibit their own unique set of immunemodulatory capabilities.
Mechanisms of macrophage recruitment and
macrophage polarization
Macrophages are among the first immune cells to
infiltrate already preinvasive tumorous lesions and
persist during the development into invasive cancer
(Clark et al., 2007). Cancer is associated with
inflammation that results in recruitment of bone
marrow derived cells (Hanahan and Weinberg, 2011;
Coussens and Werb, 2002). Growth factors like CSF-1
(colony stimulating factor 1) and vascular epithelial
growth factor (VEGF), but also monocyte chemotactic
protein-1 (MCP-1) as well as several CCL chemokines
and other molecules have been shown to induce
chemotaxis of monocytes into the tumor environment
(Lewis and Pollard, 2006). In an elegant study in three
different murine tumor models (the BALB/c 4T1
mammary tumor model, the BALB/c mammary
adenocarcinoma TS/A model and the C57BL/6 3LL
lung carcinoma model) the inflammatory Ly6Chi
monocyte subset was shown to be the major monocyte
subset to localize into the tumor and to give rise to
TAM subsets in the tumor (Movahedi et al., 2010).
With respect to the specific tumor, the molecules are
secreted by tumor cells themselves or adjacent stromal
cells. In skin carcinogenesis for example carcinogen
application induces proliferation of fibroblasts that
secrete MCP-1 which results in chemotaxis of
macrophages. Neutralization of MCP-1 almost
completely blocks this accumulation of macrophages in
the tumor (Zhang et al., 2011a). VEGF, beside its
strong angiogenic role, recruits monocytes into the
tumor microenvironment and blockade of VEGF by
bevacizumab results not only in reduced vessel density,
but also in reduced TAM infiltration (Roland et al.,
2009).
Once migrated to the tumor site monocytes
differentiate into macrophages under the influence of
macrophage colony-stimulating factor (M-CSF).
Further tumor cell-derived factors drive macrophage
polarization into one of the TAM subpopulations
described below. In general the induction of a TAM
related phenotype has been brought in context with
tumor cell derived mediators such as M-CSF (Duluc et
al., 2007), IL-4, IL-10, IL-6 (Duluc et al., 2007; Song
et al., 2009), transforming growth factor β (TGF-β1),
prostaglandin E2 (PGE2) (Lewis and Pollard, 2006;
Heusinkveld et al., 2011), hyaluron fragments (Kuang
et al., 2007) and the leukemia inhibitory factor (LIF)
(Duluc et al., 2007). In cervical cancer, monocytes are
skewed from a DC towards a macrophage phenotype
by the production of PGE2 and IL-6 from tumor cells
(Heusinkveld et al., 2011; Kim et al., 2011).
As stated above, the terms "classically activated" and
"alternatively
activated
wound
healing"
are
counterintuitive in the description of tumor-associated
Current concepts of tumor
associated macrophages
Macrophages play a prominent role in the stromal and
leukocyte compartment in malignancy and distinct
macrophage subsets in cancer have been described
(Mantovani et al., 2008; Pollard, 2009; Grivennikov et
al., 2010; Mantovani et al., 2010a). As macrophages in
human cancer can neither be classified into classical
activated M1-like or alternatively activated M2-like
macrophages they are termed tumor-associated
macrophages (TAMs). Macrophages represent a cell
type with an extreme functional plasticity enabling
them to integrate and respond to different stimuli (Stout
et al., 2009). Despite profound functional differences
between human and murine macrophages, most
functional properties of TAM subtypes have been
studied in murine cancer models due to the difficulty to
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Mallmann MR, et al.
macrophages as the conditions that dominate the tumor
microenvironment are rarely the same as in infection
(exceptions might be true for infectious related cancers
such as cervical cancer and vulvar cancer). Despite this
statement researchers attempt to classify tumorassociated macrophages into the M1-like/M2-like
terminology as of similarities in expressed marker
profiles. It is yet unclear whether similarities between
certain tumor-associated macrophages and the M1-like
or M2-like macrophages are due to the different types
of tumors that were investigated, as proposed by some
researchers, or whether there might be a "M1-like/M2like switch" during tumor progression. Despite the vast
majority of reports describing TAM phenotypes that
share properties with M2 macrophages, TAM with
expression of both M2-like and M1-like markers have
been described as well (Biswas et al., 2006). These
TAMs show high expression of genes encoding
immunosuppressive
cytokines
(Il10,
Tgfb1),
phagocytosis-related receptors/molecules (Msr2, C1q)
and inflammatory chemokines (Ccl2, Ccl5) as well as
IFN-inducible chemokines (Cxcl9, Cxcl10, Cxcl16)
(Biswas et al., 2006). Others have shown mixed M1like (CD14+HLA-DR+) and M2-like (CD14+CD163+)
TAM infiltration (Buddingh et al., 2011). These TAMs
are sarcoma associated, but similar results exist for
carcinoma as well (Movahedi et al., 2010). Conversely
TAMs in cutaneous squamous cell carcinoma partially
express the M2-like markers CD209 and CCL18, others
express M1-like markers STAT1, IL-23, IL-12 and
CD127 and again others express markers of both M1like and M2-like macrophages (Pettersen et al., 2011).
In other carcinomas there are TAMs with a
predominantly M2-like marker expression status (Ma et
al., 2010). Typical genes that are expressed by TAMs
include IL-1, IL-6 and tumor necrosis factor α (TNF-α)
(Lewis and Pollard, 2006). In consequence, TAMs are
often termed M2-like macrophages by many researches
despite their integration of probably much more diverse
stimuli than only IL-4 and/or M-CSF which suggests
that a much more dynamic model of macrophage
activation in tumor immunology must be found to
usefully characterize TAMs (Pettersen et al., 2011).
Independent from the assignment to the M1-like or M2like macrophage class, the underlining intracellular
pathways that are activated in TAM are far from
understood. Several pathways have been shown to be
important for specific functions of TAMs, for example
an Ets2-driven transcriptional program as well as a
Wnt-signaling program have been associated with
invasion and metastasis in murine breast cancer
associated TAMs (Zabuawala et al., 2010; Ojalvo et al.,
2010).
Consequently, additional TAM subpopulations will
likely be identified with specialized tumor-associated
properties that can be allocated functionally to cancer
specific needs such as growth, invasion, angiogenesis
and metastasis.
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Pro-inflammatory and
properties of TAMs
growth
promoting
Tumor-promoting inflammation and avoidance of
immune destruction represent novel hallmarks of
cancer (Hanahan and Weinberg, 2011). Macrophages
have been shown to support tumor cell growth by the
activation of different pathways. Several soluble
growth factors, eg. IL-1, IL-6, TNF-α, TGF-β,
epidermal growth factor (EGF), platelet-derived growth
factor (PDGF) produced by macrophages have been
indicated to be involved in tumor cell growth, (Lewis
and Pollard, 2006). TNFα is produced by tumor cells
and by inflammatory cells in chronic inflammation. It
promotes cell survival by induction of anti-apoptotic
molecules via TNFR1 and TNFR2 (Lin and Karin,
2007). EGF plays an important role in murine breast
cancer (Joyce and Pollard, 2009). TAMs are major
producers of EGF, and there exists interplay between
EGF producing TAMs and EGFR expressing tumor
cells, which reciprocally produce M-CSF to support
macrophage survival and EGF production. Another
important activating pathway in TAMs is mediated by
signal transducer and activator of transcription 3
(STAT3) known to result in IL-6 expression.
This pro-inflammatory cytokine is known to induce
proliferation of malignant cells (Lin and Karin, 2007;
Grivennikov et al., 2009; Bromberg and Wang, 2009)
and IL-6 has been found to have a pivotal role in
Kaposi sarcoma, multiple myeloma, Hodgkin
lymphoma, breast cancer, ovarian cancer and others
(Osborne et al., 1999; Bommert et al., 2006; Cozen et
al., 2004; Berger, 2004; Stone et al., 2012). Opposing
roles have been attributed to TGF-β.
Whereas TGF-β might inhibit tumor growth by
reducing IL-6 secretion (Lin and Karin, 2007; Derynck
et al., 2001), enhanced TGF-β secretion is often
observed in carcinoma and is associated with enhanced
epithelial-mesenchymal transition (EMT). EMT results
in higher invasiveness of epithelial tumor cells and
metastasis due to changed expression levels of
adhesion molecules and
metalloproteinases (Derynck et al., 2001). TGF-β
production by tumor cells also induces IRAK-M
(Interleukin-1 receptor-associated kinase) a negative
regulator of Toll-like receptor signaling in TAM, which
is part of the immunosuppressive phenotype of TAM
(Standiford et al., 2011).
Immunosuppressive properties of TAMs
Immunosuppressive functions of TAMs seem to be
contradictory to the strong inflammatory tumormicroenvironment and the inflammatory properties of
macrophages. Although TAMs produce several
chemokines that are associated with inflammation in
immunity
against
pathogens,
under
sterile
inflammatory conditions in cancer these molecules
rather exert a growth promoting influence on tumor
cells. TAMs are poor producers of IL-12 but produce
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Mallmann MR, et al.
IL-10 and TGFβ (Sica et al., 2000). This effect might
be due to STAT3 activation in TAMs opposing STAT1
driven Th-1 anti-tumor responses (Allavena and
Mantovani, 2012; Yu et al., 2009). Expression of MHC
class II molecules on TAMs is actively downregulated
by tumor cell derived TGF-β1, IL-10 and PGE2 (Lewis
and Pollard, 2006).
Direct inhibition of immune responses by TAMs has
been described as well (Kryczek et al., 2006). IL-10
and TNF-α in the tumor milieu induce expression of
PD-L1 (also termed B7-H1) on the membrane of
tumor-associated macrophages. Although naïve T cells
can be stimulated via PD-L1, its most prominent role is
the inhibition of activated effector T cells through the
PD-1 receptor (Kuang et al., 2009).
Allavena and Mantovani reported an additional indirect - mechanism of creating an anti-inflammatory
tumor milieu, namely the recruitment of other noninflammatory immune cells into the tumor
microenvironment (Allavena and Mantovani, 2012). In
this context, CCL17 and CCL22 produced by TAMs
have been implicated to predominantly attract Th2 and
Tregs that are non-cytotoxic cells (Allavena and
Mantovani, 2012; Mantovani et al., 2010b).
Macrophage-derived CCL18 recruits rather naïve T
cells that are primed under immune regulatory
conditions (Schutyser et al., 2002). In a murine model
of colorectal cancer, F4/80+ TAMs were found to
secrete large amounts of CCL20 attracting CCR6+ Treg
cells to the tumor side (Liu et al., 2011).
revealed that especially invasive TAMs are a unique
subpopulation of TAMs exhibiting increased WNT
signaling and promoting carcinoma cell motility
(Ojalvo et al., 2010).
Whereas the CSF-1/EGF signaling axis seems to
promote invasiveness in certain cancer models, in
others an important role in invasiveness has been
attributed to EMT (Thiery, 2002). Expression of
mesenchymal markers is correlated with TAM
infiltration in a F9-teratocarcinoma model and
depletion of macrophages results in a decrease of
mesenchymal associated genes (Bonde et al., 2012).
Moreover, growth of tumor cells in macrophageconditioned media results in EMT and enhanced
invasiveness. EMT can be induced in cancer cells in
vitro by addition of TGF-β to the cell culture and
experimental data suggest that TGF-β is also the
driving force of macrophage-induced EMT in vivo
(Derynck et al., 2001; Bonde et al., 2012).
Lymphangiogenesis promoting properties of
TAMs
Depending on the tumor characteristics tumors show
either a lymphatic or a haematogenic metastasis
pattern. Degree of lymphangiogenesis predicts poor
clinical prognosis in most malignant diseases. Tumor
cells themselves show considerable production of
lymphangiopoietic vascular endothelial growth factors
(VEGF)-C and -D. In addition, macrophages can
produce high amounts of VEGF-C and VEGF-D and
macrophage infiltration is associated with peritumoral
lymphangiogenesis in lung adenocarcinoma and
cervical cancer (Zhang et al., 2011b; Utrera-Barillas et
al., 2010). Schoppmann et al. identified a subset of
VEGFR-3+ tumor-associated macrophages that stains
for VEGF-C- and VEGF-D in human cancer probably
being the main producers of these lymphangiopoietic
factors (Schoppmann et al., 2002; Schoppmann et al.,
2006). In SCC, VEGF-C expression is associated with
CD68+ CD163+ TAMs, whereas other immune cells
infiltrating the tumor such as CD3+ T cells or CD11c+
DC do not express this lymphangiogenesis marker
(Moussai et al., 2011). In line with this, inhibition of
VEGFR-3 signaling suppresses lymphangiogenesis in
cancer and metastasis to regional lymph nodes (He et
al., 2002). Moreover in mice models of inflammationinduced lymphangiogenesis, macrophages were found
to form lymphatic-like tubes in vitro. Moreover they
showed the ability to assemble into lymphatic vessels
that arose de novo and expressed classical lymphatic
endothelial markers such as LYVE-1, VEGFR-3,
podoplanin and Prox-1 (Maruyama et al., 2005).
Invasion and metastasis promoting properties of
TAMs
Several macrophage-associated mechanisms in the
tumor microenvironment exist that support invasion
and metastasis of tumor cells. An invariant property of
tissue macrophages is the production of matrix
metalloproteinases, cathepsins and other proteolytic
enzymes that degrade the extracellular matrix
(Vasiljeva et al., 2006; Hagemann et al., 2004). While
useful in wound healing this macrophage function
subsequently allows tumor cells to invade and spread
locally. Invasion is a prerequisite for metastasis as one
of the major hallmarks of malignancy. As shown in the
PyMT mouse tumor model, the property of tumor cells
to invade tissues is dependent on macrophages
(Goswami et al., 2005; Wyckoff et al., 2004). By
producing CSF-1 and TNF-α, tumor cells recruit
macrophages which produce metalloproteinases 2, 3, 7,
and 9. Invasion of tumor cells is prominently
accompanied by coordinated migration of macrophages
(Goswami et al., 2005; Wyckoff et al., 2004). Intravital
imaging has provided direct evidence that perivascular
macrophages in mammary tumors are involved in the
intravasation of cancer cells (Wyckoff et al., 2007).
Moreover, either inhibition of EGF signaling or
deletion of macrophages can reduce the number of
tumor cells that enter the blood stream (Lewis and
Pollard, 2006). Further molecular investigations
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Angiogenesis promoting properties of TAMs
Cancer requires angiogenesis beyond a tumor size of a
few millimeters. Hypoxic conditions in immunity
against pathogens are frequent and macrophages have
adapted to this condition by a specific genetic program
under the control of the transcription factor family
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Macrophages in human cancer: Current and future aspects
Mallmann MR, et al.
hypoxia-inducible factor HIF (Leek et al., 2002).
Cancer angiogenesis is not dependent on one
mechanism, but several pathways have been described.
The neoangiogenesis in cancer development is known
as "angiogenic switch". In general cancer cells have
been shown to induce this angiogenic switch by
production of angiogenic factors the most prominent
being VEGF.
Nevertheless angiogenesis is positively correlated with
macrophage infiltration in various studies suggesting a
possible role for this cell subset in angiogenesis
(Rogers and Holen, 2011; Murdoch et al., 2008; Clear
et al., 2010). In macrophages HIF-1 is induced under
hypoxic conditions in the tumor microenvironment
resulting in the production of pro-angiogenic
molecules.
Several macrophage derived molecules that are directly
angiogenic (among those are VEGF, TNF-α, IL-8,
CXCL8 and bFGF) and others that modulate
angiogenesis (e.g. MMP2, MMP-7, MMP-9, MMP-12,
COX-2) have been described (Lewis and Pollard,
2006).
The most well-known element is VEGF that is
produced by a specialized subset of TAMs in hypoxic
areas of breast cancer (Lewis and Pollard, 2006).
In murine tumor models these VEGF-producing cells
can be identified by Tie-2 expression (De Palma et al.,
2005).
Mechanisms of modulation of angiogenesis other than
VEGF comprise the Wnt-pathway dependent
production of Flt1, an inhibitor of angiogenesis, in
myeloid cells (Stefater et al., 2011), neurotrophin 5,
FGF13, PDGFRα and Bv8 (Shojaei et al., 2007a;
Shojaei et al., 2007b, Dong et al., 2004). Experimental
mouse models using clodrolip depletion of TAMs have
shown that macrophage depletion results in drastic
reduction of vessel density and decrease in tumor
growth (Zeisberger et al., 2006).
Figure 1: Induction of TAMs in the tumor microenvironment. Circulating monocytes are recruited into the tumor by growth factors
and chemokines. Local presence of M-CSF causes the differentiation of monocytes to macrophages. Soluble tumor derived factors
initiate the polarization of macrophages into TAMs leading to the expression of molecules that support angiogenesis, tumor growth and
metastasis. Conversely TAMs secrete factors that induce local immune suppression by recruitment of Treg cells or suppress T cell
responses directly.
that this dichotomy is an oversimplification as necrosis
can induce local immunosuppression as well as certain
types of apoptosis are immunogenic which has been
shown to be related to translocation of calreticulin to
the cell surface (Vakkila and Lotze, 2004; Casares et
al., 2005; Obeid et al., 2007). Immunogenic tumor cell
death is thought to be a prerequisite for a contribution
of the immune system to the eradication of cancer cells,
called "bystander effect" (Zitvogel et al., 2006; Lake
and van der Most, 2006). In the past, this effect has
mainly been attributed to dendritic cells and T cells
Future concepts of tumor
associated macrophages (TAM)
The Role of TAMs in Chemotherapy Resistance
Most of the functions that are attributed to TAMs are
pro-tumoral, e.g. tumor progression, vascularization,
invasion and metastasis. Cell death of cancer cells upon
exposure to chemotherapy can occur in an
immunogenic or a non-immunogenic way, in the past
thought to be represented by necrosis and apoptosis,
respectively (Zitvogel et al., 2008). New data suggest
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(Zitvogel et al., 2008; Storkus and Falo, 2007). In
contrast, recent evidence suggests that macrophages are
involved in the resistance of malignant tumors against
chemotherapy. Cancer cells that are exposed to certain
chemotherapy
regimen
secrete
macrophage
chemoattractant protein-1 (MCP-1) that results in the
recruitment of MSF1 receptor expressing monocytes
and macrophages into the tumor (Geller et al., 2010;
Denardo et al., 2011). Blockade of macrophage
infiltration by blockade of CSF1 receptor results in a
partial depletion of TAMs with consecutive decrease of
tumor progression, lung metastasis and vessel density
in a murine model of breast cancer (Denardo et al.,
2011). The emerging role of macrophages in
chemotherapy resistance follows reports on the role of
other leukocyte subsets for chemotherapy responses
(Zitvogel et al., 2008). These first results identify a
chemoprotective TAM subset and raise the possibility
of targeting or reprogramming these chemoprotective
TAMs to improve efficiency of standard anticancer
treatments (De Palma and Lewis, 2011).
Therapeutic depletion of TAMs
TAM infiltration in tumors is associated with bad
prognosis and besides repolarization of macrophages,
therapeutic depletion might be an attractive approach
against invasion, angiogenesis, tumor growth and
metastasis as well. For depletion of macrophages,
clodronate-encapsulated liposomes are most often used
in the experimental murine setting. Depletion of TAMs
by this method in mouse models has been shown to
significantly inhibit tumor growth (Zeisberger et al.,
2006).
Moreover, recent studies suggest that medications with
proven clinical benefit exert part of their action through
inhibition
or
depletion
of
macrophages.
Bisphosphonates are mainly used to treat osteoporosis
and have been shown to lower the incidence of bone
metastases in multiple myeloma, breast and prostate
cancer (Rogers and Holen, 2011). Bisphosphonates
mainly affect osteoclasts, but macrophages that arise
from the same precursors are affected as well. In
macrophages bisphosphonates induce apoptosis in vitro
and inhibit M-CSF induced proliferation (Rogers and
Holen, 2011). Moreover, in murine models, the
bisphosphonate zoledronic acid decreased macrophage
infiltration into the tumor, VEGF expression and
macrophage associated MMP-9 expression (Giraudo et
al., 2004; Tsagozis et al., 2008).
Depletion of macrophages was shown to decrease
tumor growth in various murine cancer models: in
murine lung cancer, depletion of macrophages results
in a reduction of macrophage infiltration with reduction
of bone metastasis; in murine breast cancer,
macrophage infiltration and neo-vascularization is
impaired and a shift from M2-like to M1-like
phenotype is observed; in teratocarcinoma and
rhabdomyosarcoma, depletion of macrophages results
in reduction of tumor volume and reduction of blood
vessel density, respectively (Rogers and Holen, 2011).
Moreover, depletion of macrophages has been shown to
increase response to chemotherapy, for example
sorafenib in a murine model of metastatic liver cancer.
In this model, sorafenib induced macrophage
recruitment is inhibited by concomitant application of
zoledronic acid and results in decreased tumor
angiogenesis and lung metastasis (Zhang et al., 2010).
Consequently, the development of effective strategies
against cancer might target not only the cancer cell, but
also other players in the tumor microenvironment,
among which the tumor-associated macrophage plays a
prominent role.
Re-Polarization of TAMs
The plastic nature of macrophages allows to re-polarize
them into a more tumoricidal phenotype than the tumor
associated phenotype, for example the proinflammatory M1-like phenotype. Reversion of the
tumor-associated M2-like status into a M1-like
phenotype has been shown to improve anti-tumor
responses. Especially IFNg, nitric oxide and IL-12
produced by macrophages or expressed exogenously
repress tumor cell growth (Lewis and Pollard, 2006;
Peron et al., 2004). In general, this can be
accomplished by different methods. A combination of
chemotherapy with vincristine, cyclophosphamide and
doxorubicin together with immunotherapy with CpGODN led to a shift in the TAM population from a rather
M2-like towards a M1-like phenotype with
upregulation of MHC II, IFN-γ, TNF-α and IL-12
(Buhtoiarov et al., 2011). Zoledronic acid, besides its
macrophage depleting effect, has been shown to reduce
VEGF expression in TAMs as well as to induce
expression of iNOS, one of the hallmark genes of M1like polarization (Coscia et al., 2010). The histidinerich glycoprotein (HRG) skews TAM polarization
away from the M2-like to a M1-like phenotype and
suppresses placental like growth factor (PLGF) (Rolny
et al., 2011; Huang et al., 2011). Inhibition of PGE2
production in tumor cells by COX inhibitors and
blocking of IL-6 can prevent differentiation of
monocytes into M2-like macrophages in the tumor
microenvironment (Heusinkveld et al., 2011).
Interaction of already polarized M2-like macrophages
with Th1 cells results in a repolarization of M2-like
into M1-like macrophages with induction of
costimulatory molecules and production of IL-12.
Similar effects could be observed by stimulating M2like cells with CD40L+ cells and IFN-γ (Heusinkveld et
al., 2011).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
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