Review

TRENDS in Immunology Vol.23 No.11 November 2002

549

Macrophage polarization:
tumor-associated macrophages as a
paradigm for polarized M2
mononuclear phagocytes
Alberto Mantovani, Silvano Sozzani, Massimo Locati, Paola Allavena and Antonio Sica
Mononuclear phagocytes are versatile cells that can express different functional
programs in response to microenvironmental signals. Fully polarized M1 and M2
(or alternatively activated) macrophages are the extremes of a continuum of
functional states. Macrophages that infiltrate tumor tissues are driven by
tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype.
These functionally polarized cells, and similarly oriented or immature dendritic
cells present in tumors, have a key role in subversion of adaptive immunity and
in inflammatory circuits that promote tumor growth and progression.
Published online: 19 September 2002

Alberto Mantovani*
Istituto di Ricerche
Farmacologiche Mario
Negri, Via Eritrea 62,
I-20157 Milan, Italy.
Centro IDET, Institute of
General Pathology,
University of Milan,
Via Mangiagalli 31,
I-20133 Milan, Italy.
*e-mail: mantovani@
marionegri.it
Silvano Sozzani
Dept Biotechnology,
Section of General
Pathology and
Immunology, University
of Brescia, 25123 Brescia,
Italy.
Istituto di Ricerche
Farmacologiche Mario
Negri, Via Eritrea 62,
I-20157 Milan, Italy.
Massimo Locati
Centro IDET, Institute of
General Pathology,
University of Milan,
Via Mangiagalli 31,
I-20133 Milan, Italy.
Paola Allavena
Antonio Sica
Istituto di Ricerche
Farmacologiche Mario
Negri, Via Eritrea 62,
I-20157 Milan, Italy.

Cells belonging to the monocyte-macrophage lineage

have long been recognized as heterogeneous. Because
lineage-defined subsets have not been identified,
macrophage heterogeneity probably reflects the
plasticity and versatility of these cells in response to
exposure to microenvironmental signals. Cytokines
and microbial products profoundly affect the function of
mononuclear phagocytes. In particular, cytokines
associated with polarized type II responses [interleukin
(IL)-4, IL-13, IL-10] induce an alternative activation
program in macrophages. Alternatively activated[1,2]
M2 macrophages show distinct functional properties
that integrate them in polarized type II responses.
Macrophages are a major component of the
leukocyte infiltrate of tumors [3,4]. Tumor-associated
macrophages (TAMs) have complex dual functions in
their interaction with neoplastic cells (the
macrophage balance hypothesis, [3]), and evidence
suggests that they are part of inflammatory circuits
that promote tumor progression [3,4].
Here, the properties of polarized macrophages is
reviewed and recent information consistent with the
view that TAMs are a polarized M2 macrophage
population is summarized [1,2,5]. The characteristics
of dendritic cells (DCs) infiltrating neoplastic tissues
is also considered. The polarized functions of TAMs
integrate them in circuits of subversion of anti-tumor
immunity and in inflammatory mechanisms that
promote tumor growth and progression.
Properties of polarized M1 and M2 macrophages

Macrophage activation in response to microbial

agents and cytokines, interferon- (IFN-) in
http://immunology.trends.com

particular, has long been recognized [6]. More

recently, it was realized that anti-inflammatory
molecules, such as glucocorticoid hormones, IL-4,
IL-13 and IL-10, are more than simple inhibitors of
macrophage activation, in that they induce a distinct
activation program (alternatively activated
macrophages) [1,2].
Polarized macrophages differ in terms of receptor
expression, effector function and cytokine and
chemokine production (Fig. 1). For instance, arginine
metabolism is characterized by high levels of
inducible nitric oxide synthase (iNOS) in M1
macrophages, whereas the arginase pathway
predominates in the M2 cells with generation of
ornithine and polyamines. Differential cytokine
production is a key feature of polarized macrophages.
The M1 phenotype includes IL-12 and tumor necrosis
factor (TNF), whereas M2 macrophages typically
produce IL-10, IL-1 receptor antagonist (IL-1ra) and
the type II IL-1 decoy receptor. Chemokine receptors
and ligands are differentially modulated in polarized
macrophages. In particular, production of the
IFN--inducible chemokines IP-10 (CXCL10) and
MIG (CXCL9) are inhibited by IL-4 and IL-10 [7].
However, IL-4 selectively induces eotaxin-2 (CCL24)
[8], CCL18 and MDC (CCL22) in macrophages and
these effects are inhibited by IFN- [9,10]. Therefore,
differential production of chemokines that attract
Th1 (CXCL9, CXCL10) and Th2 or T regulatory (Tr)
cells (CCL22) integrates M1 and M2 macrophages in
circuits of amplification and regulation of polarized
T-cell responses.
Different inducers of M2 polarization (e.g. IL-10,
IL-4 or IL-13, glucocorticoid hormones, vitamin D3),
elicit distinct functional phenotypes in macrophages
(Fig. 1). Moreover, mononuclear phagocytes are
exposed to a multiplicity of opposing signals in vivo
with different temporal patterns. Therefore,
polarization of macrophage function should be viewed
as an operationally useful, simplified conceptual
framework describing a continuum of diverse
functional states. With this general caveat, available
information suggests that classically activated M1
macrophages are potent effector cells that kill

1471-4906/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(02)02302-5

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550

TRENDS in Immunology Vol.23 No.11 November 2002

M1

M2
Membrane receptors
Scavenger receptor A
Scavenger receptor B
CD163
MR
TLR2, TLR4
CD14

Fc-RI, II, III

(CD16, CD32, CD64)

Fc-RII (CD23)

CD80, CD86
Cytokines
TNF-
IL-1
IL-1 ra
IL-6
IL-12
IL-10
Type I IFN
Cytokine receptors
IL-1 R type I
Decoy IL-1 R type II
Chemokines

CXCL9, CXCL10,
CXCL11

CCL17, CCL22
CCL24

CCL2, CCL3,
CCL4, CCL5
CXCL8

CCL18
CCL16
Chemokine receptors
CCR7
CCR2
CXCR1, CXCR2
Effector molecules
iNOS
arginase
ROI
IFN and LPS

IL-10

IL-4 and IL-13

IL-4 and IL-13, IL-10

TRENDS in Immunology

microorganisms and tumor cells and produce copious

amounts of proinflammatory cytokines. In contrast,
M2 cells tune inflammatory responses and adaptive
Th1 immunity, scavenge debris, and promote
angiogenesis, tissue remodeling and repair.
Tumor-associated macrophages
Recruitment

TAMs derive from circulating monocytic precursors

and in situ proliferation is generally not an important
mechanism that sustains the mononuclear phagocyte
population, at least in human tumors [3]. Several
lines of evidence, including correlation between
production and infiltration in murine and human
tumors, passive immunization and gene modification,
http://immunology.trends.com

Fig. 1. M1 and M2 macrophages, the extremes of a continuum.

Essential properties of polarized macrophage populations are shown.
For M1 cells, molecules induced by IFN- and LPS are shown in green.
For M2 cells, molecules induced by IL-4 and IL-13 are shown in yellow,
those induced by IL-10 in red and those induced both by IL-4 and IL-13,
and IL-10, in blue. Macrophages exposed to the classic activation
signals, IFN- and LPS, express opsonic receptors (e.g. FcRIII/CD16),
whereas type II macrophages are characterized by abundant levels of
non-opsonic receptors (e.g. the MR). M1 cells also have a higher ratio of
reduced-to-oxidized glutathione, with opposite effects of IFN- and IL-4
on the reductive status [69]. Components of the IL-1 system are
differentially regulated in polarized macrophage populations. IL-4, IL-13
and glucocorticoid hormones induce expression of the IL-1 type II
decoy receptor, whereas IFN- and LPS inhibit it. IFN- and LPS
upregulate the signaling type I receptor, and IL-1R accessory protein
(IL-1RacP) [70]. IL-4 and IL-13 induce IL-1ra production and inhibit IL-1.
Therefore, pro- and anti-inflammatory components of the IL-1 system
are coordinately regulated by signals that polarize macrophages in a
type I or type II direction. IL-10 upregulates the CC chemokine receptors
CCR1, CCR2 and CCR5. By contrast, CXCR2 and CXCR4 are partially
downregulated under the same conditions [71]. An increase in CCR2
expression is also observed in monocytes exposed to dexamethasone
[72]. IL-4 and IL-13 do not modify the expression of CC chemokine
receptors but induce functional CXCL8 (IL-8) receptors in human
monocytes [17]. By contrast, monocytes exposed to LPS or IFN-
downregulated CCR1, CCR2 and CCR5 [30,73]. Similar to what was
reported for DCs [74], exposure of monocytes to classical
proinflammatory signals induces the expression of functional CCR7
and the effect is inhibited by IL-10 (S. Sozzani, unpublished).
Abbreviations: DC, dendritic cell; IFN, interferon; IL, interleukin;
iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide;
MR, mannose receptor; ra, receptor agonist; ROI, reactive oxygen
intermediates; TLR, toll-like receptor; TNF, tumor necrosis factor.

indicate that chemokines have a pivotal role in the

recruitment of monocytes in neoplastic tissues [3,11].
Tumors are generally characterized by the
constitutive expression of chemokines classified as
either inducible or inflammatory [7]. The molecular
mechanisms accounting for constitutive expression
have been defined only for CXCL1 and involve NFB
activation by NFB-inducing kinase [12]. This might
represent a general mechanism underlying
constitutive expression of inflammatory chemokines
in tumors.
CCL2 is probably the CC chemokine most
frequently found in tumors (sarcomas, gliomas, lung
tumors, carcinomas of the breast, cervix and ovary,
melanomas) in line with its description as a
tumor-derived chemotactic factor [3,11,13] (Fig. 2).
In a nontumorigenic melanoma, low-level CCL2
secretion, with physiological accumulation of TAMs,
promoted tumor formation, whereas high CCL2
secretion resulted in massive macrophage infiltration
and destruction of the tumor mass [14]. These results,
in a model of melanoma progression, are consistent
with the macrophage balance hypothesis [3], and
emphasize the protumor potential of levels of
macrophage infiltration similar to those observed in
human malignant lesions.
A variety of other chemokines have been detected
in neoplastic tissues as products of tumor cells or
stromal elements. These include CXCL12, CXCL8,
CXCL1, CXCL13, CCL5 [15], CCL17 and CCL22 [4].
CXCL1 and related molecules (CXCL2, CXCL3,
CXCL8 or IL-8) have an important role in melanoma
progression by stimulating neoplastic growth,

Review

Angiogenesis

TRENDS in Immunology Vol.23 No.11 November 2002

Stroma

Fibroblast

Collagen
CXCL8
CXCL1,2
VEGF
FGF2

Monocyte

DC
TGF-
CCL2

CCL20

Fibrin

IL-10
TGF-

Tissue
factor

Recruitment

MMPs

CCL18
TAM

IL-4
IL-13

Survival

MMPs

IL-10
TGF-

Polarization

VEGF
Suppression

Countercurrent
invasion

CCL2
CCL5

Tr cell

Tumor

Growth
Progression
TRENDS in Immunology

Fig. 2. TAMs as polarized M2 macrophages. TAMs are a source and target for cytokines and
chemokines in the tumor microenvironment. These molecules and other local mediators (e.g. tissue
factor, MMPs) regulate tumor growth, progression and invasion, interaction with other components
of the stroma, and the activation and orientation of adaptive immunity. Abbreviations: DC, dendritic
cell; FGF, fibroblast growth factor; IL, interleukin; M-CSF, macrophage-colony stimulating factor;
MMP, matrix metalloproteinase; TAM, tumor-associated macrophage; TGF, transforming growth
factor; Tr, regulatory T; Tu, tumor; VEGF, vascular endothelial growth factor; vMIP, viral macrophage
inflammatory protein.

promoting inflammation and inducing angiogenesis

[16]. IL-4 and IL-13 render monocytes extremely
sensitive to the neutrophil attractants CXCL8 and
CXCL1 [17] (Fig. 1). Therefore, CXCL8 and related
chemokines might contribute to regulating the
positioning and function of TAMs. Interestingly,
neutrophils are not a major constituent of the
leukocyte infiltrate, but they might have a key role in
triggering and sustaining the inflammatory cascade.
Vascular endothelial growth factor (VEGF) and
macrophage-colony stimulating factor (M-CSF) can
significantly contribute to macrophage recruitment in
tumors by promoting migration and survival [1821].
Studies in M-CSF-deficient mice (op/op) have
provided strong support to the concept of the protumor
function of the mononuclear phagocyte system. M-CSF
deficiency in op/op mice diminishes macrophage
recruitment, stroma formation and tumor growth in
the Lewis lung carcinoma model [22]. In a mammary
carcinoma model, M-CSF deficiency did not affect
early stages of tumor development but reduced
progression to invasive carcinoma and metastasis [18].
Genetic restoration of M-CSF production in epithelial
cells restored macrophage infiltration as well as
malignant behaviour.
Chemokines in tumors are more than leukocyte
attractants. Transcriptional profiling has shown that
http://immunology.trends.com

CC chemokines activate a restricted and distinct

program in monocytes [23], including matrix
metalloproteases (MMPs) and cytochrome CYP1B1,
involved in carcinogenesis. Moreover, CXC
chemokines stimulate angiogenesis [24]. Tumor cells
express receptors for chemokines [15,2527] and can
respond to these mediators with increased
proliferation and survival. Finally, chemokine-driven
leukocyte recruitment results in digestion of the
extracellular matrix that paves the way for tumor
cells leaving the primary lesions [28]. Chemokine
receptors can then guide localization of neoplastic
elements at distant anatomical sites [2527].
Intratumor differentiation

vMIPs
Tumor

Nave
T cell
Th2 cell

CCL22
CCL17

M-CSF
Growth
factors

Anergy

551

TAMs isolated from various murine tumors and from

human ovarian cancer express low levels of
inflammatory chemokine receptors, and CCR2 in
particular [29]. Downregulation of CCR2 might in
part reflect the monocyte-to-macrophage transition
and, in part, TNF- present in the ovarian cancer
microenvironment [30,31]. Downregulation of CCR2
might serve as a mechanism to localize and retain
macrophages in tumors.
IL-10, as well as transforming growth factor
(TGF)-, is produced by a variety of tumor cells and by
TAMs themselves [3236]. IL-10 promotes the
differentiation of monocytes to mature macrophages
and blocks their differentiation to DCs [37]. The effect
of IL-10 on monocyte differentiation might be an
important determinant of the relative proportion of
TAMs versus tumor-associated DCs (TADCs) and of
their relative distribution. For instance, in papillary
carcinoma of the thyroid, TAMs are evenly distributed
throughout the tissue, in contrast to DCs that are
present in the periphery [38]. To the extent that they
have been investigated, TAMs have a phenotype and
function similar to M2 macrophages. TAMs have little
cytotoxicity for tumor cells and they actually promote
tumor-cell proliferation and are also poor producers of
NO [39]. In ovarian cancer, only a minority of tumors
and, in these, a minority of macrophages localized at
the periphery, scored positive for iNOS [40]. TAMs
express high levels of the mannose receptor (MR)
(P. Allavena, unpublished) and are poor at presenting
antigen [3]. They also have an IL-10high IL-12low
cytokine repertoire.
T cells infiltrating various types of human tumors
have a type II phenotype, with a predominance of
CD8+ (e.g. Kaposis sarcoma) or CD4+ cells
(e.g. cervical carcinoma) in different neoplasms [4]. By
producing IL-4, IL-13 and IL-10, tumor-infiltrating
T cells might reinforce the skewing of monocyte
differentiation in tumors towards an M2 phenotype.
Links to adaptive immunity: the chemokine connection

Chemokines are part of the amplification and

regulation systems of polarized T-cell responses [7].
Work in gene-modified mice has shown that CCL2,
produced by tumors and TAMs, can orient specific

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TRENDS in Immunology Vol.23 No.11 November 2002

immunity in a Th2 direction, although the exact

mechanism for this action has not been defined [41].
Antibody blocking experiments have provided direct
evidence that CCL2 secretion in a poorly immunogenic
tumor blocks the generation of tumor-reactive T cells.
Reed-Sternberg cells in Hodgkins lymphoma have
been shown to express CCL22 and CCL17 [42,43].
These chemokines recognize CCR4 that is
preferentially expressed on polarized Th2 cells and on
Tr cells as well as on monocytes [7,44]. Interestingly, in
the same tumor, stromal cells produce CCL11, which
attracts eosinophils and Th2 cells. Therefore,
neoplastic elements and stroma use complementary
tools to recruit cells associated with polarized type II
responses. In the same vein, the oncogenic virus
human herpes virus 8 (HHV8), involved in the
pathogenesis of Kaposis sarcoma and hematological
malignancies, encodes three CC chemokines (vMIP-I,
II and III) which interact as agonists with CCR3,
CCR4 and CCR8 and, accordingly, preferentially
attract polarized type II T cells [4] and, presumably,
Tr cells [44]. Consistent with these in vitro
observations, Kaposis sarcoma is infiltrated by CD8+
and, to a lesser extent, CD4+ cells with a predominant
type II phenotype. Therefore HHV8-encoded
chemokines represent a strategy to subvert effective
anti-viral or anti-tumor immunity by favouring type II
responses and, possibly, Tr cells.
TAMs produce a selected set of chemokines (CCL2,
CCL22, CCL18). CCL18 produced by TAMs was
recently identified as the most abundant chemokine
in human ovarian ascites fluid [45]. CCL18 is
produced constitutively by immature DCs and by
macrophages exposed to IL-4, IL-13 and IL-10.
Because IL-4 and IL-13 are not expressed in
substantial amounts in ovarian cancer, IL-10
probably accounts for CCL18 production by TAMs.
CCL18 is an attractant for nave T cells by interacting
with an unidentified receptor [2]. Attraction of nave
T cells in a peripheral microenvironment dominated
by M2 cells and immature DCs might induce anergy.
Links to adaptive immunity: the IL-10TGF- connection

TAMs have poor antigen presenting capacity and can

suppress T-cell activation and proliferation by
releasing prostaglandins, IL-10 and TGF- [4,3236].
Moreover, they have an IL-10high IL-12low phenotype,
characteristic of M2 cells. Autocrine IL-10 accounts,
in part, for defective IL-12 production [32].
Ibe et al. have recently suggested that during
tumor establishment, T cells condition TAMs to
produce IL-10 and that inactivation of T cells results
in the induction of IFN- production and tumor
rejection [46]. TAMs display a massive and
constitutive nuclear localization of the NFB
inhibitory p50 homodimer (A. Sica, unpublished),
which probably provides a molecular mechanism for
altered TAM functions [32], including defective iNOS
expression [39,40]. The glucocorticoid-induced leucine
zipper (GILZ) transcription factor expressed at high
http://immunology.trends.com

levels in TAMs from Burkitts lymphoma [47] could

contribute to the functional phenotype of these cells.
Immature myeloid cells generated as a consequence
of the production of CSFs during tumor growth are
potent suppressors of T-cell responses. These
immature myeloid suppressors respond to undefined
attractants in head and neck squamous-cell carcinoma
[48]. The relation, if any, of immature myeloid
suppressor cells with TAMs remains to be defined.
Links to adaptive immunity: TADCs

Several reports have documented the presence of

TADCs in tumors [3,37,49]. TADCs are differentially
localized in tumors. In breast cancer, immature
langerin+ DCs are interspersed in the tumor mass,
whereas more mature CD83+, DC-LAMP+ DCs are
confined to the peritumoral area [50]. In papillary
thyroid carcinoma, TADCs were localized at the
invasion front of the tumor, unlike TAMs [38]. More
recently, ovarian tumors were reported to be
infiltrated by plasmacytoid DCs [51].
CC chemokines are probably involved in the
recruitment of DCs [49]. CCL20 is an attractant for
Langerhans-type DCs, is expressed in pancreatic
carcinoma, renal cancer, breast carcinoma and
papillary thyroid carcinoma and pancreatic cancer
[38,50,52,53]. CCL5 is an attractant for immature
DCs produced by papillary thyroid carcinoma
stimulated by hepatocyte growth factor [38]. CXCL12
is involved in the recruitment of plasmacytoid DCs to
ovarian carcinoma lesions [51].
TADCs generally show an immature phenotype with
high CD1a expression and low expression of the
costimulatory molecules CD80, CD86 and CD40 [37,38].
Mature DCs accumulate in peritumoral tissues [50],
even after chemokine gene transfer [54]. This
immature phenotype of TADCs might reflect a lack of
effective maturation signals in situ, prompt migration
to lymph nodes of mature cells or the presence of
maturation inhibitors in the tumor context (Fig. 3).
These elements might be operative to different degrees
in different tumors. For instance, in papillary thyroid
cancer, Langerhans-type DCs accumulate in regional
lymph nodes, presumably reflecting migration from
the tumor [38]. Many tumors produce IL-10, IL-6,
TGF- and M-CSF, which can block the differentiation
and maturation of DCs (Fig. 3) [37,55]. Immature DCs
might maintain tolerance to tumor antigens, and
TADCs, analogous with TAMs [3], might, in some
tumors, promote tumor progression and
dissemination. Recent results indicate that blocking
IL-10 in combination with CpG oligonucleotides
reverses the functional paralysis of TADCs with the
activation of effective anti-tumor responses [56].
Tissue remodeling, fibrosis and angiogenesis

Phagocytes have a central role in tissue remodeling

and repair during ontogenesis and adult life. This
ancestral function of mononuclear phagocytes is
expressed by TAMs that orchestrate the function of

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TRENDS in Immunology Vol.23 No.11 November 2002

Macrophage
Plasmacytoid
DC

+
M-CSF, IL-10,
IL-6

Monocyte

IL-10, IL-6
TGF-,
VEGF

Tumor and
stromal cells
IL-10,
TGF-
IL-10 low
IL-12 high
MHC high
B7 high

Myeloid DC

Mature DC

TRENDS in Immunology

Fig. 3. Accumulation and differentiation of DCs in neoplastic tissues. Both myeloid and plasmacytoid
DCs are present in tumors. Cytokines produced by tumor cells or stromal elements promote the
differentiation of precursors into macrophages rather than DCs and block DC maturation.
Abbreviations: DC, dendritic cell; IL, interleukin; M-CSF, macrophage-colony stimulating factor;
TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

other components of the tumor stroma. TAMs produce

a host of growth factors that affect tumor-cell
proliferation, angiogenesis and the deposition and
dissolution of connective tissues. These include,
epidermal growth factor (EGF), members of the
fibroblast growth factor (FGF) family, TGF-, VEGF
and chemokines.
Macrophages can produce enzymes and inhibitors
that regulate the digestion of the extracellular
matrix, such as MMPs, plasmin, urokinase-type
plasminogen activator (uPA) and the uPA receptor
Proliferation

NO,
TNF-

growth factors,
TNF-
chemokines

chemokines

VEGF, FGF2,
TNF-

TNF-, MMPs

Angiogenesis

Matrix
collagen, fibrin

Progression
Metastasis

IL-10, TGF-, PG
chemokines
Adaptive immunity
polarization, anergy, suppression
TRENDS in Immunology

Fig. 4. A simplified view of the role of TAMs in the immunobiology of tumors. Abbreviations:
FGF, fibroblast growth factor; IL, interleukin; MMP, matrix metalloproteinase; NO, nitric oxide;
PG, prostaglandin; TAM, tumor-associated macrophage; TNF, tumor necrosis factor;
TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

http://immunology.trends.com

(uPAR). Direct evidence has been presented that

MMP9 derived from hematopoietic cells of host origin
contributes to skin carcinogenesis [57,58]. MMP9 and
the uPAR are part of the transcriptional profile
activated by chemokines in monocytes [23]. MMP9
has complex effects beyond matrix degradation,
including promotion of the angiogenesis switch and
release of growth factors [57,58].
Angiogenesis is a key event in tumor growth and
progression. Macrophages can exert a dual influence
on blood vessel formation and function. Macrophages
produce molecules that are proangiogenic, and yet they
can express anti-angiogenic molecules and damage the
integrity of blood vessels. On the anti-angiogenic side,
in a murine model, CSF-induced, TAM-derived
metalloelastase generates angiostatin [59]. Uneven
vascularization and hypoxia are characteristics of
neoplastic tissues that affect macrophage distribution
and function. TAMs accumulate preferentially in the
poorly vascularized regions of tumors that are
characterized by low oxygen tension. Macrophage
migration is suppressed under hypoxic conditions [60],
and TAMs are immobilized in avascular [61] and
necrotic, hypoxic areas of tumors [62], where they
cooperate with tumor cells and promote angiogenesis
[63]. Expression of hypoxia-inducible factor-2
(HIF-2) and HIF-1 was observed in TAMs from breast
carcinoma [64,65]. These transcription factors induce
VEGF, bFGF and CXCL8, which stimulate
angiogenesis. Therefore, macrophages recruited in situ
represent an indirect pathway of amplification of
angiogenesis, in concert with angiogenic molecules
directly produced by tumor cells.
Formation of fibrous tissue and parasite
encapsulation are late events associated with
polarized Th2 responses. Fibrosis is a prominent
feature of certain human tumors. CCL2 and IL-13,
present in the tumor microenvironment as products
of tumor cells, TAMs or T cells, induce TGF-
production and fibrosis [66,67]. Therefore, it is
tempting to speculate that M2 macrophages are part
of the circuits that regulate the function of fibroblasts
in the tumor stroma.
Perspective

TAM

MMPs, TGF-
chemokines

553

Mononuclear phagocytes are versatile, plastic cells

that respond to environmental influences with the
expression of distinct transcriptional programs and
functions. The available information suggests that
macrophages that infiltrate tumors acquire the
properties of a polarized M2 phagocyte population.
The view of TAMs as a skewed M2 macrophage
population is an oversimplification. Indeed, tumors
are a diverse set of disorders, and a systematic effort
of in vitro and in vivo characterization has been made
only in selected systems (e.g. ovarian and breast
cancer for human tumors). Moreover, information
indicates that the distribution and function of TAMs
and TADCs differ considerably in different
microregions of the neoplastic tissue (peripheral

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TRENDS in Immunology Vol.23 No.11 November 2002

versus central; hypoxic versus normoxic areas). These

limitations, as well as technological developments,
call for gene expression profiling of infiltrating cells
directly obtained from different regions of different
tumors. Moreover, dynamic information in
molecularly defined models of tumor progression is at
present limited [18,57]. In spite of these limitations,
the view of a TAM as a polarized M2 macrophage is
efficacious in summarizing current understanding of
the immunobiology of these cells.
By expressing properties of polarized M2 cells, TAMs
participate in circuits that regulate tumor growth and
progression, adaptive immunity, stroma formation and
angiogenesis (Fig. 4). In particular, TAMs are a key
component of inflammatory circuits that promote
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http://immunology.trends.com

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tumor progression and metastasis [3,4,68]. The general

hypothesis of a protumor role of inflammation, and of
macrophages in particular, is supported by several lines
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infiltrating macrophages in particular, could promote
tumor progression and this raises the possibility that
the molecules and cells involved might represent novel
and valuable therapeutic targets.
Poster

For more information on macrophage development

and differentiation, see our Trends in Immunology
poster at http://archive.bmn.com/supp/imto/
posterv23i4.pdf.

regulation of expression and potential

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