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Atlas of Genetics and Cytogenetics

in Oncology and Haematology


INIST-CNRS

OPEN ACCESS JOURNAL

Deep Insight Section


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 (M). 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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Macrophages in human cancer: Current and future aspects

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 (TGF-1),
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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Macrophages in human cancer: Current and future aspects

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 (TNF-)
(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.

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)

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-, TGF-,
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). TNF 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-.
Whereas TGF- might inhibit tumor growth by
reducing IL-6 secretion (Lin and Karin, 2007; Derynck
et al., 2001), enhanced TGF- 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-
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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Macrophages in human cancer: Current and future aspects

Mallmann MR, et al.

IL-10 and TGF (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-1, 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- in the tumor milieu induce expression of
PD-L1 (also termed B7-H1) on the membrane of
tumor-associated macrophages. Although nave 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 nave 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- to the cell culture and
experimental data suggest that TGF- 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-, 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

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)

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-, 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, PDGFR 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-, TNF- 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- (Heusinkveld et
al., 2011).

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)

References
Osborne J, Moore PS, Chang Y. KSHV-encoded viral IL-6
activates multiple human IL-6 signaling pathways. Hum
Immunol. 1999 Oct;60(10):921-7
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000
Jan 7;100(1):57-70

770

Macrophages in human cancer: Current and future aspects

Mallmann MR, et al.

Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van


Damme J, Mantovani A. Autocrine production of IL-10
mediates defective IL-12 production and NF-kappa B activation
in tumor-associated macrophages. J Immunol. 2000 Jan
15;164(2):762-7

upon co-cultivation with macrophages is due to TNF-alpha


dependent up-regulation of matrix metalloproteases.
Carcinogenesis. 2004 Aug;25(8):1543-9

Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in


tumor suppression and cancer progression. Nat Genet. 2001
Oct;29(2):117-29

Peron JM, Couderc B, Rochaix P, Douin-Echinard V, Asnacios


A, Souque A, Voigt JJ, Buscail L, Vinel JP, Favre G. Treatment
of murine hepatocellular carcinoma using genetically modified
cells to express interleukin-12. J Gastroenterol Hepatol. 2004
Apr;19(4):388-96

Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002


Dec 19-26;420(6917):860-7

Vakkila J, Lotze MT. Inflammation and necrosis promote


tumour growth. Nat Rev Immunol. 2004 Aug;4(8):641-8

He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S,


Takahashi
T,
Alitalo
K.
Suppression
of
tumor
lymphangiogenesis and lymph node metastasis by blocking
vascular endothelial growth factor receptor 3 signaling. J Natl
Cancer Inst. 2002 Jun 5;94(11):819-25

Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER,


Graf T, Pollard JW, Segall J, Condeelis J. A paracrine loop
between tumor cells and macrophages is required for tumor
cell migration in mammary tumors. Cancer Res. 2004 Oct
1;64(19):7022-9

Leek RD, Talks KL, Pezzella F, Turley H, Campo L, Brown NS,


Bicknell R, Taylor M, Gatter KC, Harris AL. Relation of
hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in
tumor-infiltrative macrophages to tumor angiogenesis and the
oxidative thymidine phosphorylase pathway in Human breast
cancer. Cancer Res. 2002 Mar 1;62(5):1326-9

Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S,


Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M,
Coutant F, Mtivier D, Pichard E, Aucouturier P, Pierron G,
Garrido C, Zitvogel L, Kroemer G. Caspase-dependent
immunogenicity of doxorubicin-induced tumor cell death. J Exp
Med. 2005 Dec 19;202(12):1691-701

Schoppmann SF, Birner P, Stckl J, Kalt R, Ullrich R, Caucig


C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D. Tumorassociated macrophages express lymphatic endothelial growth
factors and are related to peritumoral lymphangiogenesis. Am
J Pathol. 2002 Sep;161(3):947-56

De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS,


Sampaolesi M, Naldini L. Tie2 identifies a hematopoietic
lineage of proangiogenic monocytes required for tumor vessel
formation and a mesenchymal population of pericyte
progenitors. Cancer Cell. 2005 Sep;8(3):211-26

Schutyser E, Struyf S, Proost P, Opdenakker G, Laureys G,


Verhasselt B, Peperstraete L, Van de Putte I, Saccani A,
Allavena P, Mantovani A, Van Damme J. Identification of
biologically active chemokine isoforms from ascitic fluid and
elevated levels of CCL18/pulmonary and activation-regulated
chemokine in ovarian carcinoma. J Biol Chem. 2002 Jul
5;277(27):24584-93

Gordon S, Taylor PR. Monocyte and macrophage


heterogeneity. Nat Rev Immunol. 2005 Dec;5(12):953-64
Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley
FJ, Stanley ER, Segall JE, Condeelis JS. Macrophages
promote the invasion of breast carcinoma cells via a colonystimulating factor-1/epidermal growth factor paracrine loop.
Cancer Res. 2005 Jun 15;65(12):5278-83

Thiery JP. Epithelial-mesenchymal transitions in tumour


progression. Nat Rev Cancer. 2002 Jun;2(6):442-54

Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita


M, Van Rooijen N, Takenaka H, D'Amore PA, Stein-Streilein J,
Losordo
DW,
Streilein
JW.
Inflammation-induced
lymphangiogenesis in the cornea arises from CD11b-positive
macrophages. J Clin Invest. 2005 Sep;115(9):2363-72

Gordon S. Alternative activation of macrophages. Nat Rev


Immunol. 2003 Jan;3(1):23-35
Ohno S, Inagawa H, Dhar DK, Fujii T, Ueda S, Tachibana M,
Suzuki N, Inoue M, Soma G, Nagasue N. The degree of
macrophage infiltration into the cancer cell nest is a significant
predictor of survival in gastric cancer patients. Anticancer Res.
2003 Nov-Dec;23(6D):5015-22

Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M,


Bottazzi B, Doni A, Vincenzo B, Pasqualini F, Vago L, Nebuloni
M, Mantovani A, Sica A. A distinct and unique transcriptional
program expressed by tumor-associated macrophages
(defective NF-kappaB and enhanced IRF-3/STAT1 activation).
Blood. 2006 Mar 1;107(5):2112-22

Berger FG. The interleukin-6 gene: a susceptibility factor that


may contribute to racial and ethnic disparities in breast cancer
mortality. Breast Cancer Res Treat. 2004 Dec;88(3):281-5

Bommert K, Bargou RC, Sthmer T. Signalling and survival


pathways in multiple myeloma. Eur J Cancer. 2006
Jul;42(11):1574-80

Cozen W, Gill PS, Ingles SA, Masood R, Martnez-Maza O,


Cockburn MG, Gauderman WJ, Pike MC, Bernstein L,
Nathwani BN, Salam MT, Danley KL, Wang W, Gage J,
Gundell-Miller S, Mack TM. IL-6 levels and genotype are
associated with risk of young adult Hodgkin lymphoma. Blood.
2004 Apr 15;103(8):3216-21

Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA,


Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W,
Kim J, Simpson AJ, Old LJ, Cui Z. Transferable anticancer
innate immunity in spontaneous regression/complete
resistance mice. Proc Natl Acad Sci U S A. 2006 May
16;103(20):7753-8

Dong J, Grunstein J, Tejada M, Peale F, Frantz G, Liang WC,


Bai W, Yu L, Kowalski J, Liang X, Fuh G, Gerber HP, Ferrara
N. VEGF-null cells require PDGFR alpha signaling-mediated
stromal fibroblast recruitment for tumorigenesis. EMBO J. 2004
Jul 21;23(14):2800-10

Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P,


Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X,
Ochoa A, Chen L, Zou W. B7-H4 expression identifies a novel
suppressive macrophage population in human ovarian
carcinoma. J Exp Med. 2006 Apr 17;203(4):871-81

Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate


targets MMP-9-expressing macrophages and angiogenesis to
impair cervical carcinogenesis. J Clin Invest. 2004
Sep;114(5):623-33

Lake RA, van der Most RG. A better way for a cancer cell to
die. N Engl J Med. 2006 Jun 8;354(23):2503-4

Hagemann T, Robinson SC, Schulz M, Trmper L, Balkwill FR,


Binder C. Enhanced invasiveness of breast cancer cell lines

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)

Lewis CE, Pollard JW. Distinct role of macrophages in different


tumor microenvironments.
Cancer
Res.
2006
Jan
15;66(2):605-12

771

Macrophages in human cancer: Current and future aspects

Mallmann MR, et al.

Schoppmann SF, Fenzl A, Nagy K, Unger S, Bayer G, Geleff


S, Gnant M, Horvat R, Jakesz R, Birner P. VEGF-C expressing
tumor-associated macrophages in lymph node positive breast
cancer: impact on lymphangiogenesis and survival. Surgery.
2006 Jun;139(6):839-46

macrophage-assisted tumor cell intravasation in mammary


tumors. Cancer Res. 2007 Mar 15;67(6):2649-56
Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M,
Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A,
Hallett M, Park M. Stromal gene expression predicts clinical
outcome in breast cancer. Nat Med. 2008 May;14(5):518-27

Vasiljeva O, Papazoglou A, Krger A, Brodoefel H, Korovin M,


Deussing J, Augustin N, Nielsen BS, Almholt K, Bogyo M,
Peters C, Reinheckel T. Tumor cell-derived and macrophagederived cathepsin B promotes progression and lung metastasis
of mammary cancer. Cancer Res. 2006 May 15;66(10):524250

Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W,


Tan B, Goldschmidt N, Iqbal J, Vose J, Bast M, Fu K,
Weisenburger DD, Greiner TC, Armitage JO, Kyle A, May L,
Gascoyne RD, Connors JM, Troen G, Holte H, Kvaloy S,
Dierickx D, Verhoef G, Delabie J, Smeland EB, Jares P,
Martinez A, Lopez-Guillermo A, Montserrat E, Campo E,
Braziel RM, Miller TP, Rimsza LM, Cook JR, Pohlman B,
Sweetenham J, Tubbs RR, Fisher RI, Hartmann E, Rosenwald
A, Ott G, Muller-Hermelink HK, Wrench D, Lister TA, Jaffe ES,
Wilson WH, Chan WC, Staudt LM. Stromal gene signatures in
large-B-cell lymphomas. N Engl J Med. 2008 Nov
27;359(22):2313-23

Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjllman AH,


Ballmer-Hofer K, Schwendener RA. Clodronate-liposomemediated depletion of tumour-associated macrophages: a new
and highly effective antiangiogenic therapy approach. Br J
Cancer. 2006 Aug 7;95(3):272-81
Zitvogel L, Tesniere A, Kroemer G. Cancer despite
immunosurveillance: immunoselection and immunosubversion.
Nat Rev Immunol. 2006 Oct;6(10):715-27

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related


inflammation. Nature. 2008 Jul 24;454(7203):436-44

Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA,


Vonderheide RH. Dynamics of the immune reaction to
pancreatic cancer from inception to invasion. Cancer Res.
2007 Oct 1;67(19):9518-27

Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of


myeloid cells in the promotion of tumour angiogenesis. Nat
Rev Cancer. 2008 Aug;8(8):618-31

Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J,


Preisser L, Anegon I, Catala L, Ifrah N, Descamps P, Gamelin
E, Gascan H, Hebbar M, Jeannin P. Tumor-associated
leukemia inhibitory factor and IL-6 skew monocyte
differentiation into tumor-associated macrophage-like cells.
Blood. 2007 Dec 15;110(13):4319-30

Tsagozis P, Eriksson F, Pisa P. Zoledronic acid modulates


antitumoral responses of prostate cancer-tumor associated
macrophages.
Cancer
Immunol
Immunother.
2008
Oct;57(10):1451-9
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological
aspects of cancer chemotherapy. Nat Rev Immunol. 2008
Jan;8(1):59-73

Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A,


Palmqvist R. High macrophage infiltration along the tumor front
correlates with improved survival in colon cancer. Clin Cancer
Res. 2007 Mar 1;13(5):1472-9

Beck AH, Espinosa I, Edris B, Li R, Montgomery K, Zhu S,


Varma S, Marinelli RJ, van de Rijn M, West RB. The
macrophage colony-stimulating factor 1 response signature in
breast carcinoma. Clin Cancer Res. 2009 Feb 1;15(3):778-87

Hammes LS, Tekmal RR, Naud P, Edelweiss MI, Kirma N,


Valente PT, Syrjnen KJ, Cunha-Filho JS. Macrophages,
inflammation and risk of cervical intraepithelial neoplasia (CIN)
progression--clinicopathological correlation. Gynecol Oncol.
2007 Apr;105(1):157-65

Bromberg J, Wang TC. Inflammation and cancer: IL-6 and


STAT3 complete the link. Cancer Cell. 2009 Feb 3;15(2):79-80
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY,
Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H,
Eckmann L, Karin M. IL-6 and Stat3 are required for survival of
intestinal epithelial cells and development of colitis-associated
cancer. Cancer Cell. 2009 Feb 3;15(2):103-13

Kuang DM, Wu Y, Chen N, Cheng J, Zhuang SM, Zheng L.


Tumor-derived
hyaluronan
induces
formation
of
immunosuppressive macrophages through transient early
activation of monocytes. Blood. 2007 Jul 15;110(2):587-95

Joyce JA, Pollard JW. Microenvironmental regulation of


metastasis. Nat Rev Cancer. 2009 Apr;9(4):239-52

Lin WW, Karin M. A cytokine-mediated link between innate


immunity, inflammation, and cancer. J Clin Invest. 2007
May;117(5):1175-83

Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, Zheng L.


Activated monocytes in peritumoral stroma of hepatocellular
carcinoma foster immune privilege and disease progression
through PD-L1. J Exp Med. 2009 Jun 8;206(6):1327-37

Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L,


Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N,
Mtivier D, Larochette N, van Endert P, Ciccosanti F,
Piacentini M, Zitvogel L, Kroemer G. Calreticulin exposure
dictates the immunogenicity of cancer cell death. Nat Med.
2007 Jan;13(1):54-61

Pollard JW. Trophic macrophages in development and


disease. Nat Rev Immunol. 2009 Apr;9(4):259-70

Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S,


Fuh G, Gerber HP, Ferrara N. Tumor refractoriness to antiVEGF treatment is mediated by CD11b+Gr1+ myeloid cells.
Nat Biotechnol. 2007a Aug;25(8):911-20

Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT,
Sadegh L, Sullivan JP, Shames DS, Brekken RA. Inhibition of
vascular endothelial growth factor reduces angiogenesis and
modulates immune cell infiltration of orthotopic breast cancer
xenografts. Mol Cancer Ther. 2009 Jul;8(7):1761-71

Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard


D, Bais C, Peale FV, van Bruggen N, Ho C, Ross J, Tan M,
Carano RA, Meng YG, Ferrara N. Bv8 regulates myeloid-celldependent tumour angiogenesis. Nature. 2007b Dec
6;450(7171):825-31

Song L, Asgharzadeh S, Salo J, Engell K, Wu HW, Sposto R,


Ara T, Silverman AM, DeClerck YA, Seeger RC, Metelitsa LS.
Valpha24-invariant NKT cells mediate antitumor activity via
killing of tumor-associated macrophages. J Clin Invest. 2009
Jun;119(6):1524-36

Storkus WJ, Falo LD Jr. A 'good death' for tumor immunology.


Nat Med. 2007 Jan;13(1):28-30

Stout RD, Watkins SK, Suttles J. Functional plasticity of


macrophages: in situ reprogramming of tumor-associated
macrophages. J Leukoc Biol. 2009 Nov;86(5):1105-9

Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER,


Segall JE, Pollard JW, Condeelis J. Direct visualization of

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)

772

Macrophages in human cancer: Current and future aspects

Mallmann MR, et al.

Yu H, Pardoll D, Jove R. STATs in cancer inflammation and


immunity: a leading role for STAT3. Nat Rev Cancer. 2009
Nov;9(11):798-809

and mast cells in lymphangiogenesis and angiogenesis in


cervical carcinogenesis. Exp Mol Pathol. 2010 Oct;89(2):190-6
Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B,
Srinivasan R, Rosol TJ, Fernandez S, Huang K, Leone G,
Ostrowski MC. An ets2-driven transcriptional program in tumorassociated macrophages promotes tumor metastasis. Cancer
Res. 2010 Feb 15;70(4):1323-33

Biswas SK, Mantovani A. Macrophage plasticity and interaction


with lymphocyte subsets: cancer as a paradigm. Nat Immunol.
2010 Oct;11(10):889-96
Clear AJ, Lee AM, Calaminici M, Ramsay AG, Morris KJ,
Hallam S, Kelly G, Macdougall F, Lister TA, Gribben JG.
Increased angiogenic sprouting in poor prognosis FL is
associated with elevated numbers of CD163+ macrophages
within the immediate sprouting microenvironment. Blood. 2010
Jun 17;115(24):5053-6

Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX,
Kong LQ, Wang L, Wu WZ, Tang ZY. Depletion of tumorassociated macrophages enhances the effect of sorafenib in
metastatic liver cancer models by antimetastatic and
antiangiogenic effects. Clin Cancer Res. 2010 Jul
1;16(13):3420-30

Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti


C, Holen I, Mnkknen H, Boccadoro M, Forni G, Musiani P,
Bosia A, Cavallo F, Massaia M. Zoledronic acid repolarizes
tumour-associated macrophages and inhibits mammary
carcinogenesis by targeting the mevalonate pathway. J Cell
Mol Med. 2010 Dec;14(12):2803-15

Zhou Q, Peng RQ, Wu XJ, Xia Q, Hou JH, Ding Y, Zhou QM,
Zhang X, Pang ZZ, Wan DS, Zeng YX, Zhang XS. The density
of macrophages in the invasive front is inversely correlated to
liver metastasis in colon cancer. J Transl Med. 2010 Feb
8;8:13

Geller MA, Bui-Nguyen TM, Rogers LM, Ramakrishnan S.


Chemotherapy induces macrophage chemoattractant protein-1
production in ovarian cancer. Int J Gynecol Cancer. 2010
Aug;20(6):918-25

Bronkhorst IH, Ly LV, Jordanova ES, Vrolijk J, Versluis M,


Luyten GP, Jager MJ. Detection of M2-macrophages in uveal
melanoma and relation with survival. Invest Ophthalmol Vis
Sci. 2011 Feb;52(2):643-50

Gordon S, Martinez FO. Alternative activation of macrophages:


mechanism and functions. Immunity. 2010 May 28;32(5):593604

Buddingh EP, Kuijjer ML, Duim RA, Brger H, Agelopoulos K,


Myklebost O, Serra M, Mertens F, Hogendoorn PC, Lankester
AC, Cleton-Jansen AM. Tumor-infiltrating macrophages are
associated with metastasis suppression in high-grade
osteosarcoma: a rationale for treatment with macrophage
activating agents. Clin Cancer Res. 2011 Apr 15;17(8):2110-9

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation,


and cancer. Cell. 2010 Mar 19;140(6):883-99
Ma J, Liu L, Che G, Yu N, Dai F, You Z. The M1 form of tumorassociated macrophages in non-small cell lung cancer is
positively associated with survival time. BMC Cancer. 2010
Mar 25;10:112

Buhtoiarov IN, Sondel PM, Wigginton JM, Buhtoiarova TN,


Yanke EM, Mahvi DA, Rakhmilevich AL. Anti-tumour synergy
of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN
immunotherapy through repolarization of tumour-associated
macrophages. Immunology. 2011 Feb;132(2):226-39

Mantovani A, Garlanda C, Allavena P. Molecular pathways and


targets in cancer-related inflammation. Ann Med. 2010a
Apr;42(3):161-70

DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL,


Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA,
Rugo HS, Hwang ES, Jirstrm K, West BL, Coussens LM.
Leukocyte complexity predicts breast cancer survival and
functionally regulates response to chemotherapy. Cancer
Discov. 2011 Jun;1(1):54-67

Mantovani A, Savino B, Locati M, Zammataro L, Allavena P,


Bonecchi R. The chemokine system in cancer biology and
therapy. Cytokine Growth Factor Rev. 2010b Feb;21(1):27-39
Movahedi K, Laoui D, Gysemans C, Baeten M, Stang G, Van
den Bossche J, Mack M, Pipeleers D, In't Veld P, De Baetselier
P, Van Ginderachter JA. Different tumor microenvironments
contain functionally distinct subsets of macrophages derived
from Ly6C(high) monocytes. Cancer Res. 2010 Jul
15;70(14):5728-39

De Palma M, Lewis CE. Cancer: Macrophages


chemotherapy. Nature. 2011 Apr 21;472(7343):303-4

Hanahan D, Weinberg RA. Hallmarks of cancer: the next


generation. Cell. 2011 Mar 4;144(5):646-74
Heusinkveld M, de Vos van Steenwijk PJ, Goedemans R,
Ramwadhdoebe TH, Gorter A, Welters MJ, van Hall T, van der
Burg SH. M2 macrophages induced by prostaglandin E2 and
IL-6 from cervical carcinoma are switched to activated M1
macrophages by CD4+ Th1 cells. J Immunol. 2011 Aug
1;187(3):1157-65

Niino D, Komohara Y, Murayama T, Aoki R, Kimura Y,


Hashikawa K, Kiyasu J, Takeuchi M, Suefuji N, Sugita Y,
Takeya M, Ohshima K. Ratio of M2 macrophage expression is
closely associated with poor prognosis for Angioimmunoblastic
T-cell lymphoma (AITL). Pathol Int. 2010 Apr;60(4):278-83
Ojalvo LS, Whittaker CA, Condeelis JS, Pollard JW. Gene
expression analysis of macrophages that facilitate tumor
invasion supports a role for Wnt-signaling in mediating their
activity in primary mammary tumors. J Immunol. 2010 Jan
15;184(2):702-12

Huang Y, Snuderl M, Jain RK. Polarization of tumor-associated


macrophages: a novel strategy for vascular normalization and
antitumor immunity. Cancer Cell. 2011 Jan 18;19(1):1-2
Kamper P, Bendix K, Hamilton-Dutoit S, Honor B, Nyengaard
JR, d'Amore F. Tumor-infiltrating macrophages correlate with
adverse prognosis and Epstein-Barr virus status in classical
Hodgkin's lymphoma. Haematologica. 2011 Feb;96(2):269-76

Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney


A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald
A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J,
Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors
JM, Staudt LM, Chan WC, Gascoyne RD. Tumor-associated
macrophages and survival in classic Hodgkin's lymphoma. N
Engl J Med. 2010 Mar 11;362(10):875-85

Kim SW, Kim JS, Papadopoulos J, Choi HJ, He J, Maya M,


Langley RR, Fan D, Fidler IJ, Kim SJ. Consistent interactions
between tumor cell IL-6 and macrophage TNF- enhance the
growth of human prostate cancer cells in the bone of nude
mouse. Int Immunopharmacol. 2011 Jul;11(7):862-72

Utrera-Barillas D, Castro-Manrreza M, Castellanos E,


Gutirrez-Rodrguez M, Arciniega-Ruz de Esparza O, GarcaCebada J, Velazquez JR, Flores-Resndiz D, HernndezHernndez D, Bentez-Bribiesca L. The role of macrophages

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)

limit

Liu J, Zhang N, Li Q, Zhang W, Ke F, Leng Q, Wang H, Chen


J, Wang H. Tumor-associated macrophages recruit CCR6+
regulatory T cells and promote the development of colorectal

773

Macrophages in human cancer: Current and future aspects

Mallmann MR, et al.

cancer via enhancing CCL20 production in mice. PLoS One.


2011 Apr 29;6(4):e19495

Karp M, Pollard JW, Yamaguchi T, Ferrara N, Gerhardt H,


Lang RA. Regulation of angiogenesis by a non-canonical WntFlt1 pathway in myeloid cells. Nature. 2011 May
29;474(7352):511-5

Moussai D, Mitsui H, Pettersen JS, Pierson KC, Shah KR,


Surez-Farias M, Cardinale IR, Bluth MJ, Krueger JG,
Carucci JA. The human cutaneous squamous cell carcinoma
microenvironment is characterized by increased lymphatic
density and enhanced expression of macrophage-derived
VEGF-C. J Invest Dermatol. 2011 Jan;131(1):229-36

Zhang J, Chen L, Xiao M, Wang C, Qin Z. FSP1+ fibroblasts


promote skin carcinogenesis by maintaining MCP-1-mediated
macrophage infiltration and chronic inflammation. Am J Pathol.
2011a Jan;178(1):382-90

Murray PJ, Wynn TA. Protective and pathogenic functions of


macrophage subsets. Nat Rev Immunol. 2011 Oct
14;11(11):723-37

Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF.
Tumor-associated macrophages infiltration is associated with
peritumoral lymphangiogenesis and poor prognosis in lung
adenocarcinoma. Med Oncol. 2011b Dec;28(4):1447-52

Pettersen JS, Fuentes-Duculan J, Surez-Farias M, Pierson


KC, Pitts-Kiefer A, Fan L, Belkin DA, Wang CQ, Bhuvanendran
S, Johnson-Huang LM, Bluth MJ, Krueger JG, Lowes MA,
Carucci JA. Tumor-associated macrophages in the cutaneous
SCC microenvironment are heterogeneously activated. J
Invest Dermatol. 2011 Jun;131(6):1322-30

Zhang W, Wang L, Zhou D, Cui Q, Zhao D, Wu Y. Expression


of tumor-associated macrophages and vascular endothelial
growth factor correlates with poor prognosis of peripheral T-cell
lymphoma, not otherwise specified. Leuk Lymphoma. 2011c
Jan;52(1):46-52

Rogers TL, Holen I. Tumour macrophages as potential targets


of bisphosphonates. J Transl Med. 2011 Oct 17;9:177

Allavena P, Mantovani A. Immunology in the clinic review


series; focus on cancer: tumour-associated macrophages:
undisputed
stars
of
the
inflammatory
tumour
microenvironment. Clin Exp Immunol. 2012 Feb;167(2):195205

Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon


C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier
S, Dresselaer T, kerud P, De Mol M, Salomki H, Phillipson
M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich
U, Van Ginderachter JA, De Palma M, Dewerchin M,
Claesson-Welsh L, Carmeliet P. HRG inhibits tumor growth
and metastasis by inducing macrophage polarization and
vessel normalization through downregulation of PlGF. Cancer
Cell. 2011 Jan 18;19(1):31-44

Bonde AK, Tischler V, Kumar S, Soltermann A, Schwendener


RA. Intratumoral macrophages contribute to epithelialmesenchymal transition in solid tumors. BMC Cancer. 2012
Jan 24;12:35
Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, BottsfordMiller J, Rupaimoole R, Armaiz-Pena GN, Pecot CV, Coward
J, Deavers MT, Vasquez HG, Urbauer D, Landen CN, Hu W,
Gershenson H, Matsuo K, Shahzad MM, King ER, Tekedereli I,
Ozpolat B, Ahn EH, Bond VK, Wang R, Drew AF, Gushiken F,
Collins K, DeGeest K, Lutgendorf SK, Chiu W, LopezBerestein G, Afshar-Kharghan V, Sood AK. Paraneoplastic
thrombocytosis in ovarian cancer. N Engl J Med. 2012 Feb
16;366(7):610-8

Sconocchia G, Zlobec I, Lugli A, Calabrese D, Iezzi G,


Karamitopoulou E, Patsouris ES, Peros G, Horcic M, Tornillo L,
Zuber M, Droeser R, Muraro MG, Mengus C, Oertli D, Ferrone
S, Terracciano L, Spagnoli GC. Tumor infiltration by FcRIII
(CD16)+ myeloid cells is associated with improved survival in
patients with colorectal carcinoma. Int J Cancer. 2011 Jun
1;128(11):2663-72
Standiford TJ, Kuick R, Bhan U, Chen J, Newstead M,
Keshamouni VG. TGF--induced IRAK-M expression in tumorassociated macrophages regulates lung tumor growth.
Oncogene. 2011 May 26;30(21):2475-84

This article should be referenced as such:


Mallmann MR, Schmidt SV, Schultze JL. Macrophages in
human cancer: Current and future aspects. Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(10):765-774.

Stefater JA 3rd, Lewkowich I, Rao S, Mariggi G, Carpenter AC,


Burr AR, Fan J, Ajima R, Molkentin JD, Williams BO, Wills-

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)

774

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