Tumor-Associated Macrophage: Its Role in Tumor
Chun-Chung Lee, Ko-Jiunn Liu, and Tze-Sing Huang1
National Institute of Cancer Research, National Health Research Institutes, Taipei, Taiwan
Macrophages are important cells in wound healing, providing aids for tissue cell
growth, tissue matrix remodeling and angiogenesis. Solid tumor comprises not only
tumor cells, but also tissue matrix and many stromal cells such as fibroblasts and
macrophages. Accumulating research results have suggested tumor-associated
macrophages (TAMs) functioning in tumor cell proliferation, tumor cell migration and
invasion, and tumor angiogenesis. In this review article, we review data from clinical
investigations and animal studies to demonstrate the association of TAMs with tumor
angiogenesis. We also discuss results of several mechanistic studies to provide pos-
sible mechanisms for TAMs-associated angiogenesis. By interacting with cancer cells,
TAMs can be induced to express more cytokines and tissue matrix-degrading enzymes,
such as matrix metalloproteinases, plasminogen activators and cathepsin B, that are
either direct angiogenic factors or tissue matrix modulators responsible for promoting
tumor angiogenesis. The angiogenic effect of TAMs can be neutralized by antagonizing
antibodies or competitive soluble receptors of interleukin-6, interleukin-8 and tumor
necrosis factor-α, suggesting the involvement of these cytokines in TAMs-associated tumor-associated
angiogenesis. With evidence indicating TAM’s tumor-promoting roles, many investiga- macrophage
tions have been undertaken to study the potential of using TAMs as the therapeutic tar- angiogenesis
get. Photosensitizer can be labeled to the scavenger receptor class A to target TAMs in
cancer photodynamic therapy. In addition, macrophages can be engineered to serve as interleukin-8
vehicles to carry drug or genes to the hypoxic areas of tumor. More detailed mecha- interleukin-6
nisms regarding the interaction between TAMs and tumor still need to be explored, and
a thorough understanding of this interaction will provide some helpful conceptual sug- tumor necrosis factor-α
gestions for the future cancer therapy.
Journal of Cancer Molecules 2(4): 135-140, 2006.
Introduction but also to participate in tissue repair process. Macrophages
can provide aids for tissue matrix remodeling, cell growth
A solid tumor is not only composed of tumor cells, rather, and angiogenesis [2,3]. Similar to macrophages in wound
it also comprises a range of stromal cells including fibro- healing, TAMs have an important role in tumor progression
blasts and inflammatory cells. An important inflammatory by exerting their multiple functions in tumor cell proliferation,
cell type commonly found in the stroma of tumor is the tu- tumor cell invasion, and tumor angiogenesis.
mor-associated macrophage (TAM2). In normal immune When a solid tumor grows beyond 2 mm in diameter, sim-
system, macrophages play an important role in wound heal- ple diffusion of oxygen and nutrients to metabolizing tissues
ing. When tissue damage occurs, macrophages infiltrate to becomes obviously insufficient. The presence of multiple
the wound not only to engulf pathogens or apoptotic cells, areas of hypoxia is a common feature of solid tumors. Many
factors are produced in the areas of hypoxia. Some of these
Received 7/18/06; Revised 8/2/06; Accepted 8/2/06 factors, such as monocyte chemotactic protein-1 (MCP-1)
Correspondence: Dr. Tze-Sing Huang, National Institute of Cancer and granulocyte-macrophage colony-stimulating factor (GM-
Research, National Health Research Institutes, 7F, No. 161, Min-Chuan CSF), are potent chemokines chemotactic toward the mono-
East Road Section 6, Taipei 114, Taiwan, Republic of China. Phone: cytes in nearby blood vessels [4,5]. Monocytes are thus
886-2-2653 4401 ext 25138. Fax: 886-2-2792 9654. E-mail: continually recruited into tumors, differentiated into TAMs,
firstname.lastname@example.org and then accumulate in the hypoxic areas (Figure 1). These
Abbreviations: TAMs, tumor-associated macrophages; MCP-1, cells have been considered to have dual effects on the tumor,
monocyte chemotactic protein-1; GM-CSF, granulocyte-macrophage
i.e. anti-tumor and pro-tumor effects . They exhibit tu-
colony-stimulating factor; HIF, hypoxia-inducible factor; PyMT,
polyoma virus middle T oncoprotein; CSF-1, colony-stimulating factor- moricidal activity toward tumor cells at initial contact, but
1; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast when they reside in the areas of hypoxia, macrophages re-
growth factor; EGF, epidermal growth factor; TGF-α, transforming spond to hypoxia by up-regulating transcriptional factors
growth factor-α; IL, interleukin; TNF-α, tumor necrosis factor-α; like hypoxia-inducible factors 1 and 2 (HIFs 1 and 2), which
MMPs, matrix metalloproteinases; tPA, tissue-type plasminogen in turn activate a broad array of genes for promoting tumor
activator; uPA, urokinase-type plasminogen activator; TGF-β, trans- cell invasion and tumor angiogenesis . Eventually, TAMs
foming growth factor-β. function as the provider of tumorigenic factors as well as
2006 MedUnion Press − http://www.mupnet.com 135
Lee et al. J. Cancer Mol. 2(4): 135-140, 2006
Figure 1: Macrophage infiltration facili-
tates tumor spreading via induction of
tumor angiogenesis and tumor cell inva-
sion. When a solid tumor grows beyond
2 mm in diameter, simple diffusion of
oxygen and nutrients to metabolizing
tissues becomes obviously insufficient.
The presence of multiple areas of hy-
poxia becomes a common feature of
solid tumors. Many factors are produced
from the areas of hypoxia. Some of the-
se factors, such as MCP-1 and GM-CSF,
are potent chemokines chemotactic
toward the monocytes in nearby blood
vessels. Monocytes are thus continually
recruited into the tumor, differentiated
into TAMs, and then accumulate in the
hypoxic areas. Macrophages respond to
hypoxia by up-regulating transcriptional
factors HIF1 and HIF2, which in turn
activate a broad array of genes for pro-
moting tumor cell invasion and tumor
angiogenesis. Eventually, TAMs function
as the provider of tumorigenic factors as
well as regulators for malignant spread-
regulators for malignant development. Accumulating evi- in a ~50% decrease of vascular density and thus the delay of
dence has suggested that high TAM infiltration is advanta- malignant transition. In contrast, enhanced recruitment of
geous to tumor spreading in certain cancers, most notably macrophages by overexpression of colony-stimulating fac-
via enhancement of tumor angiogenesis and tumor cell mi- tor-1 (CSF-1) resulted in accelerated vascularization and
gration and invasion [5,6]. This could explain why high lev- progression to malignancy [18,19]. Bingle et al. studied the
els of TAMs correlate with poor prognosis in these cancers. effect of macrophages on tumor angiogenesis by using a
mouse dorsal skinfold chamber model, which allowed direct
TAMs enhance tumor angiogenesis in human in situ visualization and monitoring of implanted tumor
spheroids and the surrounding blood vessels in vivo. Their
cancers results indicated that the presence of macrophages in tumor
spheroids resulted in at least a 3-fold increase of VEGF re-
Clinical association of TAM with tumor angiogenesis in lease and significantly greater angiogenesis .
many human cancers
The presence of inflammatory leukocytes at neoplastic Mechanistic studies for macrophages-associated angio-
tissues was firstly noted by Rudolf Virchow in 1863 . It genesis
has now been known that the majority of malignant tumors The increasing body of evidence has indicated that tumor
contain numerous macrophages as a major component of angiogenesis was induced not only by the tumor cells but
the host leukocytic infiltrate. These cells were originally also the TAMs (Figures 1 and 2)[21-24]. In vitro studies have
thought to be part of the host immune system used to de- also shown that TAMs are capable of producing a broad
fend the tumor cells, however, many clinical investigations spectrum of angiogenesis-modulating factors including
have indicated the correlation between high TAM level and growth factors, cytokines and tissue matrix-degrading en-
worse prognosis in human cancers. In Table 1, we summa- zymes [25-27].
rize a few studies of macrophage infiltration in various hu- Growth factors: A number of growth factors, including
man cancers and its relationships with tumor angiogenesis. vascular endothelial growth factor (VEGF), basic fibroblast
Several human cancers, such as breast, prostate, uterine growth factor (bFGF), epidermal growth factor (EGF), and
cervical, uterine endometrial, liver, lung, bladder, kidney, transforming growth factor-α (TGF-α), are known to be pro-
brain, and oral cancers, have been reported at least in one duced by TAMs. They are not only growth factors for tumor
study to display the significant correlation of macrophage- cells, but also potent mitogens to promote endothelial cell
infiltrating level with tumor angiogenesis [7-17]. Macro- proliferation . Among them, VEGF is well-documented
phage infiltration was also well associated with poor prog- angiogenic factor that can promote endothelial cell growth,
noses in these cancers. maturation and survival in a range of experimental systems
. VEGF is strongly expressed in glioblastoma, the most
In vivo mouse models demonstrating association of TAM frequent brain malignancy, which is characteristically highly
with tumor angiogenesis vascularized . Up-regulation of VEGF has also been ob-
In addition to the clinical correlation between increased served in human breast malignancy, and correlated with
TAM level and higher vascular density, the proangiogenic microvessel density in invasive breast carcinoma [31-34].
function of TAM has been demonstrated by experimental VEGF also functions as a monocyte chemotactic factor to
mouse models. In polyoma virus middle T oncoprotein attract TAMs to the hypoxic areas of tumor [4,5]. In addition,
(PyMT)-induced mouse mammary tumors, macrophages VEGF can cause persistent extravasation of fibrin and fi-
were recruited to the lesions where angiogenesis subse- bronectin and continuous generation of tissue matrix .
quently occurred before transition into malignant sites . Cytokines: Several inflammatory cytokines have been
Depletion of macrophages in PyMT-induced tumors resulted known to participate in macrophages-associated angiogene-
136 Print ISSN 1816-0735; Online ISSN 1817-4256
Tumor-Associated Macrophage and Tumor Angiogenesis
Table 1: Clinical association of TAM with tumor angiogenesis in many human cancers
Cancer type Description of the correlation between macrophage index and tumor angiogenesis Prognosis Ref.
Significant positive correlation was found between high vascular grade and increased macrophage
Breast cancer Poor 
Strong relationship between increased macrophage counts and reduced relapse-free and overall
The increased macrophage index was related to poor clinical outcome.
Prostate cancer A correlation was found between the volume density of TAM and tumor cell proliferation, and the Poor 
tumor area with increased macrophages exhibited higher microvessel density.
Immunohistochemical staining revealed that the localization of IL-8 was similar to that of CD68 for
cancer The prognosis of the 20 patients with high IL-8 (> 1 ng/mg protein) in uterine cervical cancers was Poor 
extremely poor. This indicates that IL-8 might be a prognostic indicator as an angiogenic factor
supplied from macrophages within and around the tumor.
Uterine endo- Infiltration of TAMs was significantly higher in tumors with deep myometrial invasion, high grade
metrial cancer and elderly patients. Poor 
Microvessel counts were strongly correlated with TAM infiltration in tumor stroma.
The mean counts of TAMs, mast cells, and tumor microvessels in hepatocellular carcinoma tissues
were significantly higher than those in pericarcinomatous liver tissues.
Liver cancer The microvessel count in the patients with metastasis was markedly higher than that without metas- Poor 
The TAM count was significantly correlated with the count of microvessels.
The macrophage density was positively correlated with the microvessel count and negatively corre-
Lung cancer lated with the patient’s relapse-free survival. Poor 
The TAM count in invasive bladder cancer was significantly higher than in superficial bladder can-
The microvessel count in invasive bladder cancer was also significantly higher than in superficial
Bladder cancer There was a positive correlation between TAM count and microvessel count. Poor 
Patients with a high TAM count (≥ 67) showed significantly higher rates of cystectomy, distant
metastasis and vascular invasion than those with a lower TAM count (< 67).
The survival rate was significantly lower in patients with a high TAM count than those with a low
The prognosis of patients without metastasis was poor for the high TAM group even when levels of
Kidney cancer microvessel were low. These findings suggest that TAMs facilitate the growth of renal cell carcino- Poor 
ma via angiogenesis and other mechanisms.
Numbers of infiltrating macrophages and small vessel density were higher in glioblastoma than in
Brain tumor astrocytoma or anaplastic astrocytoma. Poor 
Macrophage infiltration was closely correlated with the vascular density in human gliomas.
Malignant uveal A high number of macrophages were associated with the presence of epithelioid cells, heavy pig-
melanoma mentation, and high microvessel density. Poor 
The 10-year melanoma-specific mortality rate was increased with higher numbers of macrophages.
A significantly higher number of CD68-positive cells were noted in oral cancer. TAM level was
Oral cancer significantly associated with stage of invasion, microvessel density, and angiogenic factors. These Poor 
findings suggest that TAMs possibly play a role in angiogenesis during oral cancer progression.
sis during the wound healing process [3,25,26]. Interleukin-8 of activated macrophages, supporting the role of TNF-α as
(IL-8) is mitogenic to endothelial cells and stimulates angio- an angiogenic molecule from macrophages . In addition,
genesis in animals . The conditioned media of macro- macrophages are an important source of interleukin-6 (IL-6).
phages have been observed to achieve the same effects, and IL-6 is involved in macrophage-mediated wound healing, but
the effects can be markedly abolished by anti-IL-8 antibody, thus far the evidence revealing its angiogenic activity is still
suggesting that IL-8 produced by macrophages plays an lacking. Several in vitro studies reported that IL-6 had no
important role in macrophage-associated angiogenesis . effect or even growth-inhibitory effect on endothelial cells
Tumor necrosis factor-α (TNF-α) is also one of the major [42,43]. However, IL-6 expression was noted to transiently
cytokines involved in macrophage-associated angiogenesis. coincide with the onset of early events of vascular formation
during embryonic development of mice, suggesting that IL-6
TNF-α was postulated to be used by macrophages to kill
could play some role in vasculogenesis . IL-6 can syner-
cancer cells and cause tumor necrosis. When overexpress-
gize with other cytokines to promote the generation of new
ed in endothelial cells, TNF-α was growth-inhibitory and blood vessel, or it can contribute to the vascular formation
even cytotoxic to endothelial cells [37,38]. In contrast, ex- by modulating the tissue matrix via induction or activation of
ogenous application of TNF-α promoted formation of new target proteins like matrix metalloproteinases (MMPs). In
blood vessels in several in vivo models [39,40]. Leibovich et regards of tumor development, the inflammatory modules
al. further showed that anti-TNF-α antibodies completely exploited in wound healing have suggested many concepts
neutralized the angiogenic activity in the conditioned media and clues for the research of tumor angiogenesis. The ex-
2006 MedUnion Press − http://www.mupnet.com 137
Lee et al. J. Cancer Mol. 2(4): 135-140, 2006
Figure 2: Multiple factors involved in
TAMs-associated tumor angiogenesis.
For solid tumors, tumor angiogenesis is
an essential process for continuous
tumor growth and spreading. Tumor
angiogenesis can be regulated by a
complex interaction between cancer cells
and TAMs that produces angiogenic
factors and tissue matrix modulating
factors. Angiogenic factors exert direct
effects on endothelial cells. Tissue ma-
trix is also involved in regulating angio-
genesis. It is a supporting matrix for
vessels but a barrier for protruding or
migrating endothelial cells. Tissue ma-
trix is also a reservoir of angiogenic
factors. Many angiogenic factors, such
as VEGF, bFGF and TGF-β, have an affin-
ity for heparin and thus are sequestered
by tissue matrix by binding to heparin-
like glycosaminoglycans. Tissue matrix
modulating factors are not only respon-
sible for tissue matrix remodeling, they
are also capable of regulating the release
of matrix-binding angiogenic factors
following the degradation of tissue ma-
pression of IL-6, IL-8 and TNF-α can be significantly en- of TAMs-induced angiogenesis . Furthermore, several
hanced in macrophages when co-cultivated with cancer cells, studies have been undertaken to investigate the possibilities
but whether these cytokines are involved in TAM-associated of suppressing secretion of angiogenic factors by TAMs and
tumor angiogenesis needs to be verified by more studies. blocking macrophage infiltration into the tumor mass as
Endothelial cells can be induced to display the morphology anti-cancer strategies. For example, a low dose of inter-
of capillary tubes and form a network structure on Matrigel, feron-γ has been shown to inhibit secretion of TNF-α by
which can be an in vitro marker of angiogenesis . VEGF macrophages . The compound chloroquine inhibits TNF-
is a typical potent inducer in this assay system. To demon- α gene transcription in macrophages . Chemokine in-
strate TAM’s angiogenic activity, we mixed human breast hibitors affect tumor growth by decreasing TAM infiltration
cancer MCF-7 cells and macrophages in Matrigel and found . In addition, transplanted tumors transfected with In-
that interaction between cancer cells and macrophages can terleukin-10 show markedly less macrophage infiltration
produce sufficient factors for promoting endothelial cell than their non-transfected counterparts . The anti-
network formation . Furthermore, this effect of cancer angiogenic agent linomide, by suppressing functions of
cells/macrophages interaction on endothelial cells can be macrophages, exhibits its efficacy to significantly reduce
inhibited by incubation with either anti-IL-8 receptor antago- tumor volume in a murine prostate cancer model .
nizing antibody or IL-6 or TNF-α soluble receptor, suggest- Legumain, a member of the asparaginyl endopeptidase fam-
ing that IL-8, TNF-α and IL-6 indeed participate in TAMs- ily, is overexpressed by TAMs and thus serves as a target
related angiogenesis . molecule. A legumain-based DNA vaccine was shown to
Tissue matrix-degrading proteinases: Macrophages are a drastically reduce TAM density in tumor and resulted in a
rich source of tissue matrix-degrading enzymes and inhibi- marked decrease in angiogenic factors produced by TAMs
tors. They are capable of producing MMPs (e.g., MMP-2, .
MMP-7, MMP-9, and MMP-12), serine proteinases (such as With the seemingly important role of TAMs in not only tu-
plasminogen activators uPA and tPA), cysteine proteinase mor angiogenesis but also tumor cell migration/invasion, the
(e.g., cathepsin B), and plasminogen activator inhibitors to TAMs themselves become an appealing target for cancer
modulate the destruction and re-construction of tissue ma- therapeutic approaches. Hamblin et al. applied TAMs as the
trix [5,18,25,26]. Tissue matrix has some roles in regulating target of cancer photodynamic therapy . Photodynamic
angiogenesis. It is a supporting matrix for vessels but a therapy combines a non-toxic photosensitizer with harmless
barrier for protruding or migrating endothelial cells. Tissue visible light of the specific wavelength to excite photosensi-
matrix is also a reservoir of angiogenic factors. Many angi- tizer to a high-energy triplet state that will subsequently
ogenic factors, such as VEGF, bFGF and TGF-β, have an generate reactive oxygen species to kill target cells. They
affinity for heparin and thus are sequestered in tissue matrix carried out highly specific targeting of photosensitizer to
by binding to heparin-like glycosaminoglycans (Figure 2). macrophages via conjugation of a photosensitizer to a
Once the tissue matrix is proteolytically degraded, these ligand of the scavenger receptor class A, and the illumina-
factors are released and become angiogenic. In addition, tion was confined to the tumor. It was assumed that only
some proteolytic products of tissue matrix, e.g., fibrin of TAMs would be killed, and circulating monocytes and
plasmin and fragments of hyaluronic acid, can also facilitate macrophages in other tissues might still have beneficial anti-
angiogenesis [47,48]. tumor effects such as extinguishing micrometastasis [56,57].
Because TAMs migrate and accumulate in hypoxic areas
TAMs as the target for anti-cancer studies of tumor, they may serve as vectors to carry genes or drugs
into these sites to be activated by hypoxia. The potential of
Tumor angiogenesis is one of the major mechanisms by developing such a delivery strategy is to overcome the
which TAMs exert their tumor-promoting activity, and there- problem that most drugs or gene therapy vectors are difficult
fore agents that can antagonize the angiogenic factors se- to reach the tumor sites with low or even no vascular density.
creted by TAMs would be obviously effective in the inhibition Griffiths et al. generated macrophages infected with adeno-
138 Print ISSN 1816-0735; Online ISSN 1817-4256
Tumor-Associated Macrophage and Tumor Angiogenesis
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