Review

Distinct Role of Macrophages in Different Tumor Microenvironments

1

Claire E. Lewis and Jeffrey W. Pollard

1
Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, United Kingdom and 2Center
for the Study of Reproductive Biology and Womens Health, Departments of Developmental and Molecular Biology and Obstetrics &
Gynecology and Womens Health, Albert Einstein College of Medicine, Bronx, New York

tumor-derived chemoattractants are thought to ensure this ongoing

recruitment, including colony-stimulating factor-1 (CSF-1 also
known as M-CSF), the CC chemokines, CCL2, CCL3, CCL4, CCL5,
and CCL8, and vascular endothelial growth factor (VEGF). The
levels of many of these proteins in human tumors correlate
positively with the numbers of TAMs present in those tumors (3).
That these cells might help to drive tumor progression has been
inferred over a number of years from studies looking at the link
between TAM levels and prognosis. Although a few have correlated
high TAM numbers with good prognosis, the majority have linked
such numbers to reduced patient survival (Table 1). Indeed, high
TAM numbers have been shown to be an independent prognostic
factor in many forms of cancer (2). These observations accord well
with the results of animal studies using macrophage-depleted
mice to investigate the role of macrophages in tumor progression
in vivo. For example, we used mice homozygous for a null
mutation in the CSF-1 gene to deplete macrophages in a mouse
model for breast cancer. In this model, mammary tumors are
initiated by the mammary epithelial restricted expression of the
polyoma virus middle T oncoprotein (PyMT). Macrophage
depletion resulted in slower progression of preinvasive lesions to
malignant lesions and reduced formation of lung metastases (4).
Similarly, a recent study using small interfering RNA to inhibit
CSF-1 expression by MCF-7 xenografts confirmed these findings,
showing that lower numbers of TAMs are accompanied by a
marked reduction in tumor growth and angiogenesis (5).
In this review, we will review how the general phenotype of
macrophages in tumors differs from that seen in nonmalignant
tissues, and then how their migration into distinct tumor sites
exposes them to different microenvironmental signals that
educate them to perform functions that are required by tumor
cells in those areas. We will then discuss the possible therapeutic
implications of these and the ways in which TAMs could be
targeted in new anti-inflammatory therapies.

Abstract
Macrophages are prominent in the stromal compartment of
virtually all types of malignancy. These highly versatile cells
respond to the presence of stimuli in different parts of tumors
with the release of a distinct repertoire of growth factors,
cytokines, chemokines, and enzymes that regulate tumor
growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs
promote cancer cell motility, stromal and perivascular areas
where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This
review will discuss the evidence for differential regulation of
TAMs in these microenvironments and provide an overview of
current attempts to target or use TAMs for therapeutic
purposes. (Cancer Res 2006; 66(2): 605-12)

Introduction
Compelling evidence has emerged in recent years for macrophages playing an important role in tumor cell invasion into
surrounding normal tissues, proliferation and survival, and
metastasis to local and distant sites. The onset and maintenance
of tumor angiogenesis also seems to be driven, in part, by these
cells. Macrophages are derived from CD34 + bone marrow
progenitors that continually proliferate and shed their progeny
into the bloodstream as promonocytes. They then develop into
monocytes and extravasate into tissues where they differentiate
into a specific type of resident tissue macrophage (1). The
phenotype of these fully differentiated, resident macrophages can
vary markedly within tissues, from that of microglial cells in the
brain, Kupffer cells in the liver, and Langerhans cells in the skin.
Despite these regional differences, resident macrophages share a
set of common functions, including their ability to guard against
microbial infections, to regulate normal cell turnover and tissue
remodeling, and to help repair sites of injury (1).
Macrophages also form a major component of the inflammatory
infiltrate seen in both primary and secondary tumors (2), where, as
will be seen below, they also exhibit a distinct phenotype and are
termed tumor-associated macrophages (TAM). Monocytes enter
tumors through blood vessels throughout the life span of tumors,
from early-stage tumor nodules that are beginning to vascularize to
late-stage tumors that are invasive and metastatic. A number of

TAM Phenotypes
TAMs have been studied in some detail with some studies
describing their phenotype as relatively immature, characterized
by low expression of the differentiation-associated macrophage
antigens, carboxypeptidase M and CD51, high constitutive expression of interleukin (IL)-1 and IL-6, and low expression of tumor
necrosis factor-a (TNF-a; refs. 6, 7). However, it is not known yet
whether the expression of these markers by TAMs varies between
different tumors and within specific areas of tumors.
Macrophages derived from healthy or inflamed tissues are
capable of lysing tumor cells, presenting tumor-associated
antigens to T cells, and expressing immunostimulatory cytokines
to stimulate the proliferation and antitumor functions of T cells
and natural killer (NK) cells in vitro. In stark contrast, macrophages from experimental or human tumors show greatly reduced
levels of these activities, possibly due in part to their exposure to

Note: J.W. Pollard is the Sheldon and Betty E. Feinberg Senior Faculty Scholar in
Cancer Research.
Requests for reprints: Claire E. Lewis, Academic Unit of Pathology, Division of
Genomic Medicine, Floor E, The Henry Wellcome Laboratories for Medical Research,
University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, United
Kingdom. Phone: 44-114-271-2903; Fax: 44-114-226-1464; E-mail: Claire.lewis@
sheffield.ac.uk.
I2006 American Association for Cancer Research.
doi:10.1158/0008-5472.CAN-05-4005

www.aacrjournals.org

605

Cancer Res 2006; 66: (2). January 15, 2006

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Cancer Research

(14). Further experiments are required to identify the relationship,

if any, between EGF and TNF-a signaling in cross-talk between
TAMs and tumor cells and to show whether TAMs modulate
tumor cell invasion in the same manner in vivo.
Tumor growth. TAM infiltration positively correlates with
tumor cell proliferation as measured by MIB-1 levels in breast
carcinomas (15), Ki67 levels in endometrial carcinomas (16), or
mitotic index in renal cell carcinoma (17). Indeed, various studies
have shown that TAMs express a number of factors that stimulate
tumor cell proliferation and survival, including EGF (14, 18),
platelet-derived growth factor, TGF-h1, hepatocyte growth factor,
and basic fibroblast growth factor (bFGF; Fig. 2; ref. 19).
Accordingly, when cocultured with tumor cells, macrophages
secrete substances that stimulate tumor cell proliferation (20, 21).
Moreover, macrophage depletion studies indicate that the presence
of TAMs is essential for the growth of various types of experimental
tumors in vivo (22). The production of such factors by macrophages in wounds may also help to explain why some tumors
(e.g., tumors induced by injections of the Rous sarcoma virus) form
more efficiently at sites of wounding or tissue injury. This
phenomenon is known to involve factors like TGF-h1 being
expressed by inflammatory cells in wounded tissues (23). However,
it remains to be seen whether TGF-h1 and/or other molecules
specifically expressed by macrophages in these sites are centrally
involved in the development of wound-induced tumors.
Other proteins secreted by TAMs have also been implicated in
tumor growth, such as MMP-9, which is essential for the growth of
human ovarian tumors in nude mice (24). However, these effects may
be indirect rather than direct via stimulation of tumor angiogenesis
(see below). Also, the role of TAMs in tumor growth may vary
by tumor type, because in CSF-1 knockout mice neither the
incidence nor the early growth of PyMT-induced benign mammary
tumors is adversely affected by macrophage depletion, although
growth of more advanced carcinoma stages is impeded (4).3
Tumor angiogenesis. It is now widely accepted that the growth
and spread of malignant tumors requires angiogenesis, the process
by which new blood vessels sprout from the existing vasculature.
Considerable evidence indicates that TAMs play an important part in
regulating angiogenesis. The possibility that macrophages might be
capable of modulating angiogenesis was first proposed by Sunderkotter et al. (25) in 1991. We and others have since elaborated on this
to provide a detailed picture of the possible mechanisms used by
macrophages to regulate angiogenesis in tumors (Fig. 2; ref. 26).
TAMs release a number of potent proangiogenic cytokines and
growth factors, such as VEGF, TNF-a, IL-8, and bFGF. Additionally, they express a broad array of angiogenesis-modulating
enzymes, including MMP-2, MMP-7, MMP-9, MMP-12, and cyclooxygenase-2 (COX-2; refs. 2527). TAM production of MMP-9 has
been shown to be crucial for angiogenesis in a mouse model of
human cervical carcinogenesis (estrogen-treated K14-HPV16
female transgenic mice; ref. 28). Interestingly, as an important
source of MMP-2 and MMP-9 in tumors, TAM may also contribute
to the vascular normalization that occurs in tumors shortly after
their treatment with inhibitors of VEGF signaling (29). The many
proangiogenic functions of TAM may help explain reported
correlations between increased TAM numbers and high vascular
grades of many tumor types, including in breast carcinoma
(22, 30), malignant uveal melanoma (31), glioma (32), squamous

Table 1. High numbers of TAMs correlate with survival in

different forms of cancer
Favorable
prognosis

Reference

Poor
prognosis

Reference

Stomach
Colorectal
Melanoma

(59)
(72)
(73)

Breast*,c
Prostate*
Endometrial*
Bladder*,c
Kidney*
Esophageal
Superficialc
Squamous cell carcinoma*
Malignant uveal melanoma*
Follicular lymphoma

(15, 37)
(35)
(36)
(34)
(17)
(50)
(33)
(31)
(75)

*Correlation with increased tumor angiogenesis.

cCorrelation with increased involvement of local lymph nodes. No

correlation with survival was found in colon carcinoma (70), high-grade
astrocytomas (71), lung carcinoma (74), or cervical carcinoma (76).

such tumor-derived molecules as IL-4, IL-10, transforming growth

factor-h1 (TGF-h1), and prostaglandin E2 (PGE2; ref. 8). Moreover,
Mantovani et al. (9) have proposed that exposure to IL-4 and IL-10
in tumors may actually induce TAMs to develop into polarized
type II (alternatively activated) or M2 macrophages. These cells
have poor antigen-presenting capability, produce factors that
suppress T-cell proliferation and activity, and are generally better
adapted to scavenging debris, promoting angiogenesis, and
repairing and remodeling wounded/damaged tissues. This phenotype contrasts markedly with the phenotype of classically activated
type I or M1 macrophages that are efficient immune effector cells
able to kill microorganisms and tumor cells, present antigen, and
produce high levels of T-cell stimulatory cytokines (9).

Roles of TAM in Tumor Progression

Tumor invasion. In PyMT-induced mammary tumors, macrophages are present in areas of basement membrane breakdown
and invasion during the development of early-stage lesions
(Fig. 1A; ref. 4). This finding, together with other results showing
the up-regulation of proteolytic enzymes like cathepsin B in
macrophages present at the same locations (10), indicates that
TAMs could be involved in the invasion of tumor cells into
surrounding normal tissue. Indeed, Hagemann et al. (11) have
reported that coculturing macrophages with tumor cells enhances
their invasive properties in a manner dependent on TNF-a and
matrix metalloproteinases (MMP). Subsequently, it was shown in
Matrigel invasion assays that TNF-a acted by stimulation of the
c-Jun-NH2-kinase and nuclear factor-nB signaling pathways (12).
Downstream targets included such proinvasive target genes as
MIF and extracellular MMP inducer (EMMPRIN) in tumor cells
(12). These proteins then act in turn to enhance the local release
of MMPs by macrophages and possibly other stromal cells such
as fibroblasts (12, 13). In other coculture experiments, tumor cell
invasion into a collagen matrix was increased by macrophages
that synthesized epidermal growth factor (EGF) in response to
tumor-derived CSF-1, leading to induction of several genes that
increased directional movement and invasion of the tumor cells

Cancer Res 2006; 66: (2). January 15, 2006

606

E.Y. Lin and J.W. Pollard, unpublished results.

www.aacrjournals.org

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Macrophages in Different Tumor Microenvironments

Figure 1. Location of different TAM subpopulations in tumors. TAMs were visualized by staining fixed sections of spontaneous PyMT-induced murine mammary tumors
(A, C, E, and G) or human breast carcinomas (B, D, F , and H ) using antibodies that specifically recognize the pan-macrophage markers F4/80 (murine) or CD86
(human). TAMs are seen to gather in areas of tumor cell invasion where they help to degrade the basement membrane and facilitate the migration of tumor cells into the
stroma of the surrounding tissue (A and B ), and in perivascular areas where they seem to promote metastasis by expressing factors like EGF (C and D). Other
subpopulations of TAMs are seen in hypoxic, perinecrotic (E and F ), and stromal (G and H) areas of these tumors where they promote angiogenesis and metastasis,
respectively. Bar , 50 Am; V , blood vessel; N , necrosis.

cell markers, like pimonidazole, to highlight the presence of both

transient (avascular and nonnecrotic) and chronic (perinecrotic)
areas of hypoxia in human and experimental tumors. TAMs
accumulate in such hypoxic/necrotic areas in human endometrial,
breast, prostate, and ovarian carcinomas (30, 3639). We have
also found TAMs to accumulate in such areas in PyMT-induced
mammary tumors (Fig. 1) and human prostate tumor xenografts
(3). This pattern of TAM migration is possibly due to a number of
mechanisms, including the hypoxic induction of such macrophage
chemoattractants as EMAPII, endothelin 2, and VEGF (as reviewed
in ref. 3). Furthermore, as macrophages are phagocytes, they may
also be attracted into hypoxic, perinecrotic areas along a trail of
necrotic debris emanating from such areas. Hypoxia seems to
inhibit macrophage migration, thereby immobilizing them in such
areas. Increased numbers of TAMs in these sites correlate with
increased lymph node involvement and/or poor prognosis in
breast cancer (37) and endometrial cancer (38). The increased
levels of TAMs at such sites may promote tumor progression in
part by stimulating levels of angiogenesis, such as appears to
occur in breast carcinoma (37).
TAMs respond to tumor hypoxia by up-regulating the hypoxiainducible transcription factors HIF-1 and HIF-2. Although both

cell carcinoma of the esophagus (33), bladder carcinoma (34), and

prostate carcinoma (35).
In PyMT-induced mouse mammary tumors, macrophages are
recruited to premalignant lesions immediately before the angiogenic switch that presages the transition to malignancy. Depletion
of these macrophages results in a f50% reduction in vascular
density even in tumors that progress to advanced stages. This
effect is associated with increased necrosis as would be expected
by loss of blood supply. TAMs are sufficient to induce angiogenesis in this model because premature recruitment of macrophages into benign hyperplastic lesions by CSF-1 overexpression
results in accelerated vascularization of these normally poorly
vascularized lesions along with accelerated progression to
malignancy.4
Newly formed blood vessels in tumors are often disorganized
and prone to collapse, resulting in areas of inadequate perfusion
and hypoxia (low oxygen tension). Rapid tumor cell proliferation
also outstrips the rate of new blood vessel growth, contributing to
hypoxia in some areas. A number of studies have used hypoxic

E.Y. Lin, J. Li, L. Gnatovskiy, et al., unpublished results.

www.aacrjournals.org

607

Cancer Res 2006; 66: (2). January 15, 2006

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Cancer Research

Figure 2. The roles of different subpopulations of TAMs in tumor progression. 1, invasion: TAMs secrete a variety of proteases to breakdown the basement membrane
around areas of proliferating tumor cells (e.g., ductal carcinoma in situ in the breast), thereby prompting their escape into the surrounding stroma where they
show deregulated growth. 2, angiogenesis: In areas of transient (avascular) and chronic (perinecrotic) tumor hypoxia, macrophages cooperate with tumor cells to
induce a vascular supply for the area by up-regulating a number of angiogenic growth factors and enzymes. These diffuse away from the hypoxic area and, together with
other proangiogenic stimuli in the tumor microenvironment, stimulate endothelial cells in neighboring, vascularized areas to migrate, proliferate, and differentiate
into new vessels. 3, immunosuppression: Macrophages in hypoxic areas secrete factors that suppress the antitumor functions of immune effectors within the tumor.
4, metastasis: A subpopulation of TAMs associated with tumor vessels secretes factors like EGF to guide tumor cells in the stroma toward blood vessels where
they then escape into the circulation. In the stromal compartment (both the acellular regions and others where they are in close contact with tumor cells), TAMs secrete
growth factors to stimulate tumor cell division and/or undefined factors that promote tumor cell motility.

identified up-regulation of messages encoding >30 other proangiogenic genes in primary macrophages exposed to hypoxia, including
CXCL8, angiopoietin, COX-2 (the inducible form of nitric oxide
synthase), and other factors (41).
We found recently that when macrophages are cocultured
in vitro with human tumor spheroids, they infiltrate deep into the
central, hypoxic areas of these structures. The release of VEGF by
macrophages-infiltrated spheroids was significantly higher than
that seen for noninfiltrated spheroids. This increase translated into
a significant stimulation of angiogenesis in vivo when spheroids
were implanted into microcirculation window chambers on the
flanks of nude mice for 3 days (46).
A recent report has identified a subset of monocytes that
express the angiopoietin receptor Tie-2 as important inducers of
angiogenesis in both spontaneous and orthotopic tumor models
(47). Knockout of these Tie-2-expressing cells in vivo markedly
reduced angiogenesis in human glioma xenografts and prompted
substantial tumor regression. The authors of this study propose
that Tie-2-expressing monocytes/macrophages may account for
most of the proangiogenic activity of myeloid cells that are

factors are up-regulated by macrophages exposed to hypoxia

in vitro as well as in hypoxic/necrotic areas of human tumors (40),
their relative contribution to the regulation of gene expression by
TAMs has yet to be fully elucidated. White et al. (41) used
adenoviral infection to overexpress HIF-2 in human macrophages
and found it to be the primary inducer of genes encoding
angiogenic proteins in these cells. However, the repertoire of genes
activated by overexpression of each HIF may differ from those upregulated in natural settings of hypoxia.
Macrophages also up-regulate VEGF and other proangiogenic
factors in response to hypoxia. TAMs express VEGF almost
exclusively in avascular and perinecrotic areas of human breast
carcinomas (42). Hypoxic induction of this cytokine is largely
dependent on HIF-1, at least in murine peritoneal macrophages
(43). Macrophages also synthesize elevated levels of MMP-7 when
exposed to hypoxia in vitro and in avascular areas of human
tumors (44). This multifunctional MMP has many substrates in the
extracellular matrix and basement membrane, and is known to
stimulate endothelial cell proliferation and migration, which can
support tumor angiogenesis (45). A recent cDNA array study has

Cancer Res 2006; 66: (2). January 15, 2006

608

www.aacrjournals.org

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Macrophages in Different Tumor Microenvironments

defined at least two ways that macrophages affect metastasis.

First, the motility of tumor cells away from the main body of the
tumor almost always occurs in juxtaposition to macrophages
(which seem to attract tumor cells). Second, extravasion of tumor
cells into blood vessels often occurs at clusters of macrophages
found attached to the abluminal side of the vessels. Experiments
conducted in vitro and in vivo indicate that each of these cell
types exhibit coordinated movement (14, 53). This movement
critically requires CSF-1 and EGF signaling in the macrophages
and tumor cells respectively, with the ligands being produced by
the reciprocal cell type. Inhibition of either pathway blocks cell
movement of both cell types. Furthermore, the number of tumor
cells entering the bloodstream is dramatically reduced with
reduction of macrophage number along the vessels or inhibition
of EGF signaling.6 These observations accord with those of Ohno
et al. (36) whose findings show a correspondence between the
number of macrophages in the tumor stromal compartment and
the metastatic potential of the tumor. The subpopulation of TAM
seen in close proximity to some blood vessels in both murine
mammary tumors and human breast carcinomas indicate that
they may play a similar role in these tissues (Fig. 1, C and D).
However, although macrophages isolated from human breast
tumors express abundant EGF (15), this has yet to be shown in
perivascular TAMs. Thus, it remains to be formally established
whether this subpopulation of TAMs is essential for metastasis.
Interestingly, TAMs have also been shown to express the lymphatic endothelial growth factor, VEGF-C, suggesting that they
may also promote dissemination of tumor cells by stimulating
the formation of lymphatic vessels in tumors (54).
In mouse models of PyMT-induced mammary cancer, systemic
depletion of macrophages results in reduced formation of lung
metastases (4), suggesting that systemic macrophages or TAMs
are important in the establishment of metastatic tumors. The
ability of tumor cells to colonize and grow in the lungs is
dependent on VEGF-induced expression of MMP-9 by alveolar
macrophages (and endothelial cells; ref. 55). Also, Oosterling et al.
(56) also showed a link between macrophages in metastatic sites
and the growth of metastatic tumors. These investigators
selectively depleted macrophages in the peritoneal cavity or liver
and showed that CC531 colon tumor cells injected into either the
peritoneum or liver portal vein formed tumors more slowly than
in control mice. Together, these findings suggest that macrophages at metastatic sites support tumor growth, and accords well
with clinical studies showing that increased numbers of macrophages in regional lymph node metastases correlates with poor
patient survival (57).
Immunosuppression. Unlike macrophages from healthy
tissues, which are capable of presenting tumor-associated antigens,
lysing tumor cells, and stimulating the antitumor functions of
T cells and NK cells, TAMs in the tumor microenvironment lack
these activities, leaving the host without the ability to mount an
effective antitumor immune response. A number of studies have
shown that tumor-derived molecules, like cytokines, growth
factors, chemotactic molecules, and proteases, influence TAM
functions (8, 25, 58). For example, tumor cells secrete IL-4, IL-6,
IL-10, MDF, TGF-h1, and PGE2, which inhibit the cytotoxic activity
of TAMs (8, 58). Moreover, TGF-h1, IL-10, and PGE2 may suppress

present in tumors. In support of this proposal, we have noted

that a subset of CD14+ human peripheral blood monocytes also
expresses Tie-2.5
Hypoxic areas of tumors produced by inadequate vascular
perfusion are likely to generate additional adverse conditions in
the tumor microenvironment, such as low pH and elevated levels
of lactate, which might stimulate proangiogenic gene expression in
TAMs (48, 49). Moreover, as macrophages are likely to experience a
combination (if not all) of these cellular stresses simultaneously in
ischemic areas of tumors, an investigation of their combined effect
on macrophage function is clearly warranted.
An interesting recent paper by Ohno et al. (36) confirmed that
high numbers of TAMs locating to areas of chronic hypoxia
(i.e., necrosis) in endometrial carcinomas were associated with
reduced relapse-free survival and increased myometrial invasion,
as might be expected, but also that the close proximity of TAMs
to tumor cell nests in the same tumors correlated with improved
survival. Furthermore, TAMs in the stromal compartment of
these tumors correlated positively with lymph node metastasis.
Together, these observations suggest that TAMs respond to
different signals in different areas of a tumor, promoting tumor
progression in hypoxic/necrotic areas (although angiogenesis
was not examined per se in this study), facilitating metastasis in
stromal areas, and reducing tumor cell activity in areas where
TAMs make close contact with tumor cells. The identity of the
signals present in these three tumor zones regulating these
different TAM functions have yet to be determined. However, in
model systems, macrophage responses can be influenced through
cell-to-cell contact by the type of CSF-1 expressed. For example,
in xenograft models of malignant glioma, mice died rapidly if
they were engrafted with cells transfected with the secreted form
of CSF-1 but survived if the cells expressed the cell surfacebound form of CSF-1. The survival of the mice was associated
with macrophage binding to the glioma cells followed by
subsequent killing (50, 51).
Together, the data strongly suggest that TAMs are important
modulators of angiogenesis, being involved both in the formation
of new vessels and in their remodeling into a coherent functional
network. They migrate into hypoxic/necrotic areas of the tumor
where vascularization is urgently needed for tumor cell survival,
and are then activated by local signals, like hypoxia, to
synthesize angiogenic regulators. This contributes to the
formation of new vessels, facilitating local tumor growth and
survival (Fig. 2).
Metastasis. Mounting lines of evidence also implicate TAMs in
the regulation of metastasis (Fig. 2). High numbers of TAMs in
primary tumors have been correlated with early establishment of
metastases in a number of tumor types (30, 34). TAMs seem to play
roles in both the release of metastatic cells from the primary
tumor as well as the establishment of secondary tumors at distant
sites.
As early as 1982, Gorelik et al. (52) showed that inoculation of
thioglycollate-elicited peritoneal macrophages reduced the rate of
lung clearance of several types of murine tumor cells injected i.v.
and increased the formation of metastatic lung nodules by i.v.
injected B16 melanoma or Lewis lung carcinoma cells. Furthermore, in PyMT-induced murine mammary tumors as well as in
xenografts of rat breast cancer cells, intravital imaging has

C. Murdoch and C.E. Lewis, unpublished observations.

www.aacrjournals.org

609

J. Wyckoff, Y. Wang, E.Y. Lin, et al., unpublished results.

Cancer Res 2006; 66: (2). January 15, 2006

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Cancer Research

also found in dense clusters as part of leukocytic infiltrates at areas

of focal breakdown of the basement membrane. Tumor cells are
thus able to escape the confines of the basement membranes and
migrate across into the stroma of surrounding healthy tissues,
where they, together with macrophages, stimulate angiogenesis.
These newly formed vessels sprout into the early tumor, providing
nutrients and oxygen for tumor growth and supplying multiple exit
routes for metastasizing cells. The latter may involve a subpopulation of TAMs aligned with the outer surface of tumor-associated
blood vessels and cells lying in other regions of the stromal
compartment. These vessel-associated TAMs provide chemotactic
signals for tumor cells that promote migration and intravasation
into the blood and lymphatic vasculature. A separate subpopulation of TAMs also gather at sites distant from the vasculature,
where the limited diffusion of oxygen (and possibly nutrients like
glucose) activates a quite different TAM phenotype that expresses
a broad array of proangiogenic factors. This ensures the
revascularization of each hypoxic tumor area and protects tumor
cells in these from hypoxia-induced cell death. Growth factors
secreted by TAMs in these (and possibly other) areas of tumors
then directly promote the proliferation of tumor cells. The consequence of these combined TAM-driven processes is progression of
the tumor toward a more highly angiogenic, malignant phenotype.
Thus, it seems that at least four different microenvironments
sites of initial tumor cell invasion, perivascular sites, stromal
regions, and hypoxic/necrotic areasmay educate macrophages
to carry out specific functions in support of tumor cell requirements and activities in those different areas (67). These studies
reflect the pitfalls associated with the interpretation of early TAM
studies in which these cells were isolated from whole animal or
human tumors and characterized as one phenotype in functional
in vitro assays.
However, apart from hypoxia, little is known of the microenvironmental signals that regulate the activities of subpopulations of TAMs in these different tumor sites. In vitro studies have
shown that CSF-1 synthesized locally by tumors stimulates the
expression of EGF by macrophages, causing a two-cell paracrine
loop that promotes tumor cell motility (53). It is hoped that recent
advances in the use of laser microdissection to capture cells from
specific areas of tissues sections (68) will now allow the isolation of
TAMs from such areas (and more specifically, the RNA or proteins
expressed by these cells), so that their phenotype can be more fully
characterized using DNA and/or protein microarrays. It is also not
known whether different TAM functions in such tumor sites reflect
different final differentiation states of these cells, or whether they
are entirely plastic and/or reversible, so that TAMs can express one
or more phenotypes in a temporal sequence, dependent only on
the presence or absence of local signals.
If such studies generate information on macrophage-specific
surface receptors uniquely expressed by TAMs in the most
aggressive areas of tumors (i.e., the hypoxic, stromal and/or
perivascular areas, where TAMs drive angiogenesis and metastasis,
respectively), then it might prove possible to target cytotoxic
therapies to TAMs in these specific areas, leaving other antitumor
subpopulations of TAMs and macrophages in other tissues
relatively unaffected. In addition, TAMs, through their phagocytic
capacity, might engulf liposomes carrying cytotoxic drugs and
carry them into the tumor, where, upon their death, these drugs
would be released.
Because TAMs migrate into and accumulate in hypoxic areas, it
has been postulated that these cells might be used as vectors to

the expression of MHC class II molecules by macrophages in the

tumor microenvironment as well as distant sites like the spleen
and peritoneum. This effect may limit the ability of TAMs to
present tumor-associated antigens to T cells effectively in these
areas (8). Thus, tumors undergo immunoediting to down-regulate
macrophage functions that are potentially dangerous to the tumor
even in circumstances where recognizable tumor antigens are
presented. It should be noted that the tumoricidal activity of TAMs
may vary markedly in different tumor microenvironments. For
example, in advanced gastric carcinoma, the number of TAMs in
close proximity to tumor cells in tumor cell nests correlates
positively with tumor cell apoptosis, suggesting that TAMs or TAM
effector cells are actively involved in tumor cell destruction.
Notably, tumors that have large numbers of nest TAM are
associated with a significant increase in 10-year disease-free
survival (59).
Another important aspect of TAM involvement in antitumor
immune mechanisms is the ability of these cells to release
immunostimulatory cytokines. For example, macrophage expression of IL-12, a cytokine known to stimulate both the proliferation
and cytotoxicity of T cells and NK cells (60), is markedly
suppressed in tumors, possibly by exposure to IL-10, PGE2, and
TGF-h1 (8, 61). By coinjecting mice with human prostate tumor
cells and macrophages engineered to overexpress IL-12, Satoh et al.
(62) showed that it was possible to quickly reestablish enhanced
expression of MHC in TAMs along with increased T-cell infiltration
and an antitumor immune response, resulting in a marked
reduction in the growth of both the primary tumor and lung
metastases.
Hypoxia in the tumor microenvironment is likely to contribute
to suppressing the antitumor activity of TAMs as it stimulates the
release of the potent immunosuppressive factors PGE2 and IL-10.
These factors impair the development of immune cells by acting
on the early stages of their development from primitive
pluripotent stem cells (i.e., immunopoiesis), inhibiting the
antitumor activity of any immune cells that are formed (8, 63).
Additionally, they act on TAMs to reduce their cytotoxicity activity
toward tumor cells (8, 63, 64). This may involve reduced oxygen
radical formation due to decreased substrate availability.
Hypoxia also inhibits the ability of macrophages to phagocytose
dead or dying cells and present antigens to T cells. One
mechanism by which this may be achieved is by reduction in
the surface expression of CD80, a costimulatory molecule needed
for the full activation of T-cell responses to antigenic peptides.
In contrast, hypoxia can also enhance the direct cytotoxicity of
macrophages by up-regulating release of TNF-a. As mentioned
above, TAMs also up-regulate the expression of MMP-7 protein in
hypoxic areas of tumors (44). MMP-7 is known to cleave the Fas
ligand from neighboring cells, making tumor cells not only less
responsive to chemotherapeutic agents, such as doxorubicin (65),
but also lysis by NK and T cells (66).

Conclusion
To summarize, analysis of the expression of protumor molecules
by TAMs in human tumors and functional studies in macrophagedepleted murine tumor models have shown TAMs to play an
important part in various key steps in tumor progression (Fig. 2). It
seems that in early preinvasive lesions, tumor cells release
chemokines to attract macrophages (and other inflammatory
cells) into stromal areas surrounding the tumor. Macrophages are

Cancer Res 2006; 66: (2). January 15, 2006

610

www.aacrjournals.org

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Macrophages in Different Tumor Microenvironments

their subsequent mitosis. Because macrophages are terminally

differentiated and thus nondividing cells, they are refractory to the
cytotoxic effects of the active metabolite. As a result, spheroids
infiltrated with P450-engineered macrophages displayed a significant reduction in volume and gross morphologic damage
compared with mock-engineered controls (69). These results are
encouraging but in vivo studies to test the efficacy of this new
approach for targeted gene delivery are now required.

carry genes or drugs activated by hypoxia into these sites. The

development of such a delivery system would be useful because
most drugs or gene therapy vectors applied systemically fail to
penetrate more than a few hundred micrometers from their points
of entry via blood vessels, such that tumor cells in avascular tumor
areas go largely untreated in most forms of therapy. Some limited
data has been provided recently to suggest that such a
macrophage-based system might work. Small breast tumor
spheroids have been infiltrated with macrophages infected with
adenovirus containing a hypoxia-driven prodrug-activating enzyme
(cytochrome P450). When infiltrated, spheroids were then exposed
to the corresponding prodrug, cyclophosphamide, the P450
enzyme expressed by hypoxic macrophages within spheroids
converted the prodrug into its active, cytotoxic metabolite
(4-hydroxy-cycloposphamide). This cell membranepermeable
cytotoxin then diffused from infected macrophages, intercalated
into the DNA of surrounding tumor cells, causing cell death during

References
1. Ross JA, Auger MJ. The biology of the macrophage. In:
The macrophage. 2nd ed. Burke B, Lewis CE, editors.
Oxford (United Kingdom): Oxford University Press; 2002.
2. Bingle L, Brown NJ, Lewis CE. The role of tumorassociated macrophages in tumor progression: implications for new anticancer therapies. J Pathol 2002;196:
25465.
3. Murdoch C, Giannoudis A, Lewis CE. Mechanisms
regulating the recruitment of macrophages into hypoxic
areas of tumors and other ischemic tissues. Blood 2004;
104:222434.
4. Lin EY, Nguyen AV, Russell RG, Pollard JW. Colonystimulating factor 1 promotes progression of mammary
tumors to malignancy. J Exp Med 2001;193:72740.
5. Aharinejad S, Paulus P, Sioud M, et al. Colonystimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of
human mammary tumor xenografts in mice. Cancer Res
2004;64:537884.
6. Konur A, Kreutz M, Knuchel R, et al. Three dimensional co-culture of human monocytes and macrophages
with tumor cells: analysis of macrophage differentiation
and activation. Int. J Cancer 1996;66:64552.
7. Leek RD, Harris AL. Tumour associated macrophages
in breast cancer. J Mamm Gland Biol Neoplasia 2002;7:
17789.
8. Elgert KD, Alleva DG, Mullins DW. Tumor-induced
immune dysfunction: the macrophage connection.
J Leukoc Biol 1998;64:27590.
9. Mantovani A, Sozzani S, Locati M, et al. Macrophage
polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends
Immunol 2002;23:54955.
10. Domagala W, Striker G, Szadowska A, et al. Cathepsin
D in invasive ductal NOS breast carcinoma as defined by
immunohistochemistry. No correlation with survival at
5 years. Am J Pathol 1992;141:100312.
11. Hagemann T, Robinson SC, Schulz M, et al. Enhanced
invasiveness of breast cancer cell lines upon cocultivation with macrophages is due to TNF-a dependent up-regulation of matrix metalloproteases. Carcinogenesis 2004;25:15439.
12. Hagemann T, Wilson J, Kulbe H, et al. Macrophages
induce invasiveness of epithelial cancer cells via NF-nB
and JNK. J Immunol 2005;175:1197205.
13. Tang Y, Kesavan P, Nakada MT, Yan L. Tumorstroma interaction: positive feedback regulation of
extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinasedependent generation of soluble EMMPRIN. Mol
Cancer Res 2004;2:7380.
14. Goswami S, Sahai E, Wyckoff JB, et al. Macrophages
promote the invasion of breast carcinoma cells via a

www.aacrjournals.org

Acknowledgments
Received 11/7/2005; accepted 11/9/2005.
Grant support: Biotechnology and Biological Sciences Research Council, Medical
Research Council, UK, and the Yorkshire Cancer Research, UK (C.E. Lewis); and
National Cancer Institute grants CA 94173, CA 100324, and the Cancer Center Core
grant P30 CA 13330 (J.W. Pollard).
We thank Dr. Elaine Lin (Albert Einstein College of Medicine, Bronx, NY) for
providing tissues from the different stages of PyMT tumor progression seen in Fig. 1
and Tatyana Harris for her help drawing Fig. 2.

colony-stimulating factor-1/epidermal growth factor

paracrine loop. Cancer Res 2005;65:527883.
15. Tsutsui S, Yasuda K, Suzuki K, et al. Macrophage
infiltration and its prognostic implications in breast
cancer: the relationship with VEGF expression and
microvessel density. Oncol Rep 2005;14:42531.
16. Wang FQ, So J, Reierstad S, Fishman DA. Matrilysin
(MMP-7) promotes invasion of ovarian cancer cells
by activation of progelatinase. Int J Cancer 2005;114:
1931.
17. Hamada I, Kato M, Yamasaki T, et al. Clinical effects
of tumor-associated macrophages and dendritic cells on
renal cell carcinoma. Anticancer Res 2002;22:42814.
18. Lewis CE, Harris AL, et al. Secretion of epidermal
growth factor by macrophages associated with breast
carcinoma. Lancet 1993;342:1489.
19. Lewis C, Murdoch C. Macrophage responses to
hypoxia: implications for tumor progression and anticancer therapies. Am J Pathol 2005;167:62735.
20. van Netten, George EJ, Ashmead BJ, et al. Macrophage-tumor cell associations in breast cancer. Lancet
1993;342:8723.
21. Hewlett G, Opitz HG, Flad HD, Schlumberger HD.
Macrophages/monocytes require cell-to-cell contact in
order to regulate the growth of a murine lymphoma cell
line. J Immunol 1979;123:22659.
22. Polverini PJ, Leibovich SJ. Effect of macrophage
depletion on growth and neovascularization of hamster
buccal pouch carcinomas. J Oral Pathol 1987;16:43641.
23. Sieweke MH, Thompson NL, Sporn MB, Bissell MJ.
Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-h. Science 1990;248:165660.
24. Huang S, Van Arsdall M, Tedjarati S, et al.
Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in
mice. J Natl Cancer Inst 2002;94:113442.
25. Sunderkotter C, Goebeler M, Schulze-Osthoff K, et al.
Macrophage-derived angiogenesis factors. Pharmacol
Ther 1991;51:195216.
26. Lewis CE, Leek R, Harris A, McGee JO. Cytokine
regulation of angiogenesis in breast cancer: the role of
tumor-associated macrophages. J Leukoc Biol 1995;57:
74751.
27. Klimp AH, Hollema H, Kempinga C, et al. Expression
of cyclooxygenase-2 and inducible nitric oxide synthase
in human ovarian tumors and tumor-associated macrophages. Cancer Res 2001;61:73059.
28. Giraudo E, Inoue M, Hanahan D. An aminobisphosphonate targets MMP-9-expressing macrophages
and angiogenesis to impair cervical carcinogenesis.
J Clin Invest 2004;114:62333.
29. Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular
normalization by VEGFR2 blockade governs brain tumor
response to radiation: role of oxygenation, angiopoietin-1,
and matrix metalloproteinases. Cancer Cell 2004;6:55363.

30. Leek RD, Lewis CE, Whitehouse R, et al. Association

of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 1996;56:
46259.
31. Makitie T, Summanen P, Tarkkanen A, Kivela T.
Tumor-infiltrating macrophages (CD68(+) cells) and
prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 2001;42:141421.
32. Nishie A, Ono M, Shono T, et al. Macrophage infiltration and heme oxygenase-1 expression correlate with
angiogenesis in human gliomas. Clin Cancer Res 1999;5:
110713.
33. Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S.
Significance of macrophage chemoattractant protein-1
expression and macrophage infiltration in squamous
cell carcinoma of the esophagus. Am J Gastroenterol
2004;99:166774.
34. Hanada T, Nakagawa M, Emoto A, et al. Prognostic
value of tumor-associated macrophage count in human
bladder cancer. Int J Urol 2000;7:2639.
35. Lissbrant IF, Stattin P, Wikstrom P, Damber JE,
Egevad L, Bergh A. Tumor associated macrophages in
human prostate cancer: relation to clinicopathological
variables and survival. Int J Oncol 2000;17:44551.
36. Ohno S, Ohno Y, Suzuki N, et al. Correlation of
histological localization of tumor-associated macrophages with clinicopathological features in endometrial
cancer. Anticancer Res 2004;24:333542.
37. Leek RD, Landers RJ, Harris AL, Lewis CE. Necrosis
correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br
J Cancer 1999;79:9915.
38. Burton JL, Wells JM, Corke KP, et al. Macrophages
accumulate in avascular, hypoxic areas of prostate
tumors: implications for the targeted therapeutic gene
delivery to such sites. J Pathol 2000;192:8A.
39. Negus RP, Stamp GW, Hadley J, Balkwill FR.
Quantitative assessment of the leukocyte infiltrate in
ovarian cancer and its relationship to the expression of
C-C chemokines. Am J Pathol 1997;150:172334.
40. Burke B, Tang N, Corke KP, et al. Expression of HIF1a by human macrophages: implications for the use of
macrophages in hypoxia-regulated cancer gene therapy.
J Pathol 2002;196:20412.
41. White JR, Harris RA, Lee SR, et al. Genetic
amplification of the transcriptional response to hypoxia
as a novel means of identifying regulators of angiogenesis. Genomics 2004;83:18.
42. Lewis JS, Landers RJ, Underwood JC, et al. Expression
of vascular endothelial growth factor by macrophages is
up-regulated in poorly vascularized areas of breast carcinomas. J Pathol 2000;192:1508.
43. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1a is
essential for myeloid cell-mediated inflammation. Cell
2003;112:64557.

611

Cancer Res 2006; 66: (2). January 15, 2006

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Cancer Research
44. Burke B, Giannoudis A, Corke KP, et al. Hypoxiainduced gene expression in human macrophages:
implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 2003;163:123343.
45. Nishizuka I, Ichikawa Y, Ishikawa T, et al. Matrilysin
stimulates DNA synthesis of cultured vascular endothelial cells and induces angiogenesis in vivo . Cancer Lett
2001;173:17582.
46. Bingle L, Lewis CE, Corke K, et al. Macrophages
promote angiogenesis in human breast tumour spheroids in vivo . Br J Cancer. In press 2005.
47. De Palma M, Venneri MA, Galli R. Tie2 identifies a
hematopoietic lineage of proangiogenic monocytes
required for tumor vessel formation and a mesenchymal
population of pericyte progenitors. Cancer Cell 2005;8:
21126.
48. Xiong M, Elson G, Legarda D, Leibovich SJ.
Production of vascular endothelial growth factor by
murine macrophages: regulation by hypoxia, lactate,
and the inducible nitric oxide synthase pathway. Am J
Pathol 1998;153:58798.
49. Heming TA, Dave SK, Tuazon DM, et al. Effects of
extracellular pH on tumour necrosis factor-a production by resident alveolar macrophages. Clin Sci (Lond)
2001;101:26774.
50. Jadus MR, Irwin MC, Irwin MR, et al. Macrophages
can recognize and kill tumor cells bearing the
membrane isoform of macrophage colony-stimulating
factor. Blood 1996;87:523241.
51. Jadus MR, Williams CC, Avina MD, et al. Macrophages kill T9 glioma tumor cells bearing the membrane
isoform of macrophage colony stimulating factor
through a phagocytosis-dependent pathway. Immunology 1998;160:3618.
52. Gorelik E, Wiltrout RH, Brunda MJ, et al. Augmentation of metastasis formation by thioglycollate-elicited
macrophages. Int J Cancer 1982;29:57581.
53. Wyckoff J, Wang W, Lin EY, et al. A paracrine loop
between tumor cells and macrophages is required for
tumor cell migration in mammary tumors. Cancer Res
2004;64:70229.
54. Schoppmann SF, Birner P, Stockl J, et al. Tumorassociated macrophages express lymphatic endothelial

growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002;161:94756.

55. Hiratsuka S, Nakamura K, Iwai S, et al. MMP9
induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell
2002;2:289300.
56. Oosterling SJ, van der Bij GJ, Meijer GA, et al.
Macrophages direct tumour histology and clinical
outcome in a colon cancer model. J Pathol 2005;207:147.
57. Oberg A, Samii S, Stenling R, Lindmark G. Different
occurrence of CD8+, CD45R0+, and CD68+ immune cells
in regional lymph node metastases from colorectal
cancer as potential prognostic predictors. 155. Int J
Colorectal Dis 2002;17:259.
58. Ben-Baruch A. Inflammation-associated immune
suppression in cancer: the roles played by cytokines,
chemokines and additional mediators. Semin Cancer
Biol 2005; [Epub ahead of print].
59. Ohno S, Inagawa H, Dhar DK, et al. The degree of
macrophage infiltration into the cancer cell nest is a
significant predictor of survival in gastric cancer
patients. Anticancer Res 2003;23:501522.
60. Trinchieri G, Gerosa F. Immunoregulation by interleukin-12. J Leukoc Biol 1996;59:50511.
61. Mitsuhashi M, Liu J, Cao S, et al. Regulation of
interleukin-12 gene expression and its anti-tumor
activities by prostaglandin E2 derived from mammary
carcinomas. J Leukoc Biol 2004;76:32232.
62. Satoh T, Saika T, Ebara S, et al. Macrophages
transduced with an adenoviral vector expressing
interleukin 12 suppress tumor growth and metastasis
in a preclinical metastatic prostate cancer model.
Cancer Res 2003;63:785360.
63. Wojtowicz-Praga S. Reversal of tumor-induced immunosuppression: a new approach to cancer therapy.
J Immunother 1997;20:16577.
64. Zeineddine NS, Avina MD, Williams CC, Wepsic HT,
Jadus MR. Macrophages that kill glioma cells expressing
the membrane form of macrophage colony stimulating
factor are resistant to prostaglandin E2 and interleukin10. Immunol Lett 1999;70:638.
65. Mitsiades N, Yu WH, Poulaki V, et al. Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects

Cancer Res 2006; 66: (2). January 15, 2006

612

tumor cells from chemotherapeutic drug cytotoxicity.

Cancer Res 2001;61:57781.
66. Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian
LM. Matrilysin [MMP-7] expression selects for cells with
reduced sensitivity to apoptosis. Neoplasia 2001;3:45968.
67. Pollard JW. Tumor educated macrophages promote
tumor progression and metastasis. Nat Rev Cancer 2004;
4:718.
68. Todd R, Lingen MW, Kuo WP. Gene expression
profiling using laser capture microdissection. Expert Rev
Mol Diagn 2002;2:497507.
69. Griffiths L, Binley K, Iqball S, et al. The macrophagea novel system to deliver gene therapy to
pathological hypoxia. Gene Ther 2000;7:25562.
70. Khorana AA, Ryan CK, Cox C, et al. Vascular
endothelial growth factor, CD68, and epidermal growth
factor receptor expression and survival in patients with
stage II and stage III colon carcinoma: a role for the host
response in prognosis. Cancer 2003;97:9608.
71. Rossi ML, Jones NR, Candy E, et al. The mononuclear
cell infiltrate compared with survival in high-grade
astrocytomas. Acta Neuropathol (Berl) 1989;78:18993.
72. Funada Y, Noguchi T, Kikuchi R, et al. Prognostic
significance of CD8+ T cell and macrophage and
macrophage peritumoral infiltration in colorectal cancer. Oncol Rep 2003;10:30913.
73. Piras F, Colombari R, Minerba L, et al. The predictive
value of CD8, CD4, CD68, and human leukocyte antigenD-related cells in the prognosis of cutaneous malignant
melanoma with vertical growth phase. Cancer 2005;104:
124654.
74. Johnson SK, Kerr KM, Chapman AD, et al. Immune
cell infiltrates and prognosis in primary carcinoma of
the lung. Lung Cancer 2000;27:2735.
75. Farinha P, Masoudi H, Skinnider BF, et al. Analysis of
multiple biomarkers shows that lymphoma-associated
macrophage (LAM) content is an independent predictor
of survival in follicular lymphoma (FL). Blood 2005;106:
216974.
76. Davidson B, Goldberg I, Gotlieb WH, et al. Macrophage infiltration and angiogenesis in cervical squamous cell carcinomaclinicopathologic correlation.
Acta Obstet Gynecol Scand 1999;78:2404.

www.aacrjournals.org

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.

Distinct Role of Macrophages in Different Tumor

Microenvironments
Claire E. Lewis and Jeffrey W. Pollard
Cancer Res 2006;66:605-612.

Updated version

Access the most recent version of this article at:

http://cancerres.aacrjournals.org/content/66/2/605

Cited Articles

This article cites by 71 articles, 24 of which you can access for free at:
http://cancerres.aacrjournals.org/content/66/2/605.full.html#ref-list-1

Citing articles

This article has been cited by 100 HighWire-hosted articles. Access the articles at:
http://cancerres.aacrjournals.org/content/66/2/605.full.html#related-urls

E-mail alerts
Reprints and
Subscriptions
Permissions

Sign up to receive free email-alerts related to this article or journal.

To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at pubs@aacr.org.
To request permission to re-use all or part of this article, contact the AACR Publications
Department at permissions@aacr.org.

Downloaded from cancerres.aacrjournals.org on April 25, 2015. 2006 American Association for Cancer
Research.