Role of macrophages in tumour progression

Immunology Letters 123 (2009) 97–102

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Review

Role of macrophages in tumour progression K.S. Siveen, Girija Kuttan ∗ Dept. of Immunology, Amala Cancer Research Centre, Amala Nagar Post, Thrissur 680 555, Kerala, India

a r t i c l e

i n f o

Article history: Received 24 December 2008 Received in revised form 6 February 2009 Accepted 10 February 2009 Available online 9 March 2009 Keywords: Tumour associated macrophage Invasion Metastasis Hypoxia Matrix Metalloproteinase Therapeutic intervention Prognosis

a b s t r a c t It is now becoming clear that the inflammatory cells that exist in the tumour microenvironment play an indispensable role in cancer progression. Tumour associated macrophages (TAMs) represent a prominent component of the mononuclear leukocyte population of solid tumours, which displays an ambivalent relationship with tumours. They originate in the circulation and are recruited to the tumour site by tumour-derived attractants such as chemokines and interact with the tumour cells and preferentially localize at the tumour–host tissue interface, in regions often associated with low oxygen tensions. The tumour microenvironment, including cytokines and hypoxia, regulates the localization and function of TAMs. Upon activated by cancer cells, the TAMs can release a vast diversity of growth factors, proteolytic enzymes, cytokines, and inflammatory mediators. Many of these factors are key agents in cancer metastasis. Substantial evidence suggests that TAMs can interact with cancer cells, modify the ECM, and promote cancer cell invasion and metastasis. Several natural products have shown ability to inhibit the production of proinflammatory cytokines and growth factors by TAMs. The presence of extensive TAM infiltration has been shown to correlate with cancer metastasis and poor prognosis in a variety of human carcinomas. © 2009 Elsevier B.V. All rights reserved.

1. Introduction

2. Macrophages and immunity

Inflammation is well known to play a key role in initiating and promoting cancer, while it can also contribute to both specific and innate tumour rejection [1–3]. Epidemiological studies revealed that chronic inflammation predisposes to different cancers, colon cancer being a prototype. Inflammatory responses recruit many immune cells, among which macrophages are key players [4]. The microenvironment surrounding the tumour mass contains excessively proliferating tumour cells, along with several host components that includes stromal cells, an expanding vasculature and a characteristic inflammatory infiltrate associated with the constant tissue remodeling. Experimental data demonstrates the role for these individual components in promoting tumour growth and progression. Specific examples include endothelial cells [5–7], macrophages [8–10] and cancer associated fibroblasts [11]. It appears that most components of the immune system are endowed with potential dual functions and can be considered as a doubleedged sword. Immune cells can reject tumours on one hand by producing anti-tumour cytokines, thus directly destroying tumour cells, but sometimes they are recruited and enslaved by tumour cells to help in its progression that result in bringing most patients into the clinic.

Macrophages are essential for host defence [12,13]. In primitive organisms, macrophages are the host defence, in that they are responsible for everything from recognition to engulfment to destruction of threats [14]. In higher organisms, like humans, macrophages play a crucial role in the innate and adaptive immune responses to pathogens, and are critical mediators of inflammatory processes. Macrophages are released from the bone marrow as immature monocytes and, after circulating in the blood stream, migrate into tissues to undergo final differentiation into resident macrophages, including kupffer cells in the liver, alveolar macrophages in the lung, and osteoclasts in the bone. The immunological and repair functions of macrophages are well documented. It is known that they are among the first cells to arrive at the sites of wounding and/or infection, where they perform several functions. They produce cytokines and chemokines to orchestrate the recruitment and actions of other immune cells, and produce growth factors, angiogenic factors and proteases to promote tissue repair. They also kill pathogens through the production of reactive oxygen and nitrogen radicals and present foreign antigens to cytotoxic T-cells. Macrophages are generally not tumouricidal for tumour cells unless activated, for example, by antibodies or such ‘classic’ macrophage stimulants as interferon gamma (IFN-␥) or the bacterial product, lipopolysaccharide (LPS). Once activated, direct cytotoxicity is exerted towards tumour cells, or indirect cytotoxicity via the secretion of factors that stimulate the anti-tumour functions of other cell types. Macrophages can thus

∗ Corresponding author. Tel.: +91 4872304190. E-mail address: [email protected] (G. Kuttan). 0165-2478/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.imlet.2009.02.011

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Fig. 1. Role of TAM in cancer progression. The figure represents the interaction between various chemokines leading to tumour progression and metastasis. TAM—tumourassociated macrophages; M-CSF—macrophage-colony stimulating factor; MMPs—matrix metalloproteinase; TGF—transforming growth factor; VEGF—vascular endothelial growth factor; TNF—tumour necrosis factor; FGF2—fibroblast growth factor 2; TF—tissue factor.

exhibit pro- and anti-inflammatory properties, depending on the disease stage and the signals they receive, i.e. the inflammatory balance in the microenvironment. Macrophages have a pleiotropic biological role which includes antigen presentation, target cell cytotoxicity, removal of debris and tissue remodeling, regulation of inflammation, induction of immunity, thrombosis and various forms of endocytosis [15]. In the setting of tumours, tumour associated macrophages (TAMs) have a range of functions with the capacity to affect diverse aspects of neoplastic tissues including angiogenesis and vascularization, stroma formation and dissolution, and modulation of tumour cell growth (enhancement and inhibition). When activated, they can induce neoplastic cell death (cytotoxicity, apoptosis) and/or elicit tumour destructive reactions through alterations of the tumour microvasculature [16]. Solid tumours, both primary lesions and metastases, are infiltrated by large numbers of tumour associated leukocytes. These are a heterogeneous population of cells consisting of various (and variable) subsets of T-cells (helper, suppressor and cytotoxic), B cells, natural killer (NK) cells, and macrophages. Macrophages are often prominent, comprising up to 80% of the cell mass in breast carcinoma [17]. Macrophages can assume a range of different phenotypes based on environmental stimuli [8]. The extremes of this range obtained in vitro are the M1 phenotype, associated with active microbial killing, and the M2 phenotype, associated with tissue remodeling and angiogenesis. When monocytes in tumours are exposed to tumour derived anti-inflammatory molecules like IL-4, IL-10, transforming growth factor ␤1 and prostaglandin E2, they develop into polarized or M2 macrophages. These macrophages have poor antigen presenting ability and produce factors that suppress T-cell proliferation and activity. They are better adapted to scavenging for debris, promoting angiogenesis, and repairing and remodeling wounded/damaged tissues. This contrasts markedly with the phenotype of classically activated type I or M1 macrophages that are efficient immune effector cells able to kill microorganisms and tumour cells, present antigen, and produce high levels of immunostimulatory cytokines [18]. The M2 phenotype appears to be that which dominates in tumours, as tumour associated macrophages (TAMs) show a sim-

ilar molecular and functional profile [19], that is characterized by low expression of differentiation-associated macrophage antigens such as carboxypeptidase M and CD51, high constitutive expression of interleukin IL-1 and IL-6, and low levels of tumour necrosis factor [17,20]. TAMs are derived from monocytes that are recruited largely by CCL2 (Chemokine (C–C motif) ligand 2), formerly known as monocyte chemotactic protein (MCP), and chemokines [2]. MCP is expressed mainly by tumour cells as well as by endothelial cells, fibroblasts, and macrophages in human tumours [21]. Some studies have suggested that MCP-1 may be the main determinant of the macrophage content in tumours [22] and it is highly expressed in a wide range of tumour types including glioma [23], meningioma [24], ovarian carcinoma [25], and squamous cell carcinoma of uterine cervix [26]. Other major chemoattractants involved in monocyte uptake into tumours includes macrophage-colony stimulating factor (M-CSF or CSF-1), vascular endothelial growth factor (VEGF), CCL3, CCL4, CCL5, CCL8, macrophage inflammatory protein-1 alpha (MIP-1␣) and macrophage migration inhibition factor (MIF). The levels of chemoattractant proteins in tumour mass often correlate positively with TAM numbers in human tumours [27]. 3. TAMs and invasion TAMs promote cancer metastasis through several mechanisms, including promotion of angiogenesis, induction of tumour growth, and enhancement of tumour cell migration and invasion. The mechanisms of TAMs promoting angiogenesis and tumour growth have been well reviewed by several articles [28–30]. Tumours do not grow beyond 2–3 mm3 and cannot metastasize unless vascularized [31]. The hypoxic stress in the tumour mass leads to the expression of inflammatory molecules, which promote the recruitment of macrophages followed by conversion to the M2 phenotype. TAMs are capable to modulate and induce neovascularization and functions related to stroma formation. When TAMs are activated, in response to specific stimuli, these cells can express a repertoire of substances that promote angiogenesis. Growth factors such as acidic fibroblasts growth factor (aFGF/FGF1), basic fibroblasts growth factor (bFGF/FGF2), vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (GM-CSF), transform-

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ing growth factor-␣, insulin-like growth factor-1, platelet derived growth factor (PDGF), tumour growth factor-␤ (TGF-␤) and other monokines (e.g. tumour necrosis factor-␣ (TNF-␣), interleukin-1, interleukin-6, interleukin-8, substance P, prostaglandins, interferons and thrombospondin which are released by tumour cells leads to the activation of macrophages (Fig. 1) and have the capability to influence the angiogenic process [32–34]. Angiogenesis is also facilitated by TAM-derived proteases released in tumours, as extracellular proteolysis is an absolute requirement for new blood vessel formation. Macrophages can express proteases to release a number of pro-angiogenic molecules bound to heparan sulfate in proteoglycans, and fragment of fibrin and collagen [35], which facilitate angiogenesis. Among these, matrix metalloproteases (MMPs 1, 2, 3, 9 and 12), plasmin, urokinase plasminogen activator and receptor [36] are the prominent ones which promotes tumour directed angiogenesis. MMPs are a family of matrix degrading enzymes including collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP3), matrilysin (MMP-7), gelatinase B (MMP-9), and other MMPs. The MMP expression has been implicated in tumour progression through enhancing angiogenesis, tumour invasion and metastasis [37,38]. TAMs have been reported to correlate with the metastatic potential of a variety of human cancers, and they have also been shown to be a major source of MMP-9. In addition, urokinase-type plasminogen activator is a serine protease synthesized by TAMs in various human tumour types [39]. TAMs were shown to express CXCL8, which like VEGF, binds heparin in the ECM and stimulate angiogenesis [40,41]. Thus TAMs have the capacity to affect each phase of the angiogenic process, including degradation of the extracellular matrix, endothelial cell proliferation and endothelial cell migration. The levels of urokinase-type plasminogen activator have been shown to correlate with reduced relapse-free and overall survival in cancer [42]. TAMs can also secrete cysteine-type lysosomal proteases and a wide variety of growth factors that can stimulate cancer growth.

4. Effect of hypoxia on TAM New blood vessels in tumours are usually disorganized and prone to collapse, resulting in areas of inadequate perfusion and hypoxia (low oxygen tension). Additionally, rapid tumour cell proliferation in some areas may outpace the rate of new blood vessel growth, causing hypoxic areas to form [43,44]. The level of TAMs in tumours appears to be affected by hypoxia, a trait commonly found in these tissues. TAM numbers are generally higher in tumours containing high overall levels of hypoxia, as seen in primary human breast carcinomas [45] and various animal tumours [46]. Recent evidence has shown that TAMs may accumulate in high numbers in hypoxic/necrotic areas of endometrial [47], breast [46], prostate [48] and ovarian [49] carcinoma due to the hypoxic release of such macrophage chemoattractants as EMAP-II, endothelin 2, and VEGF [27]. These findings suggest that hypoxic tumours secrete higher amounts of chemoattractants and/or other factors that enhance monocyte attachment to and migration through the tumour vasculature. Once targeted to hypoxic sites, TAM functions are greatly affected by hypoxia-related factors. Because macrophages are phagocytes, they may also be attracted to hypoxic, perinecrotic areas along a trail of necrotic debris emanating from dead cells. Hypoxia also entraps TAMs by decreasing their mobility in a number of ways. One such approach involves the hypoxic up-regulation of the enzyme mitogen-activated protein kinase phosphatase (MKP-1) by macrophages [50]. This is important because various chemoattractant receptors, including those for

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CCL2, VEGF, and endothelin 2, stimulate cell migration by phosphorylating the signaling enzymes MEK, ERK1/2, and p38 MAPK. Up-regulated MKP-1 rapidly dephosphorylates these molecules in TAMs, thus terminating the chemotactic response of TAMs to these chemokines [27,51,52]. Hypoxia also inhibits macrophage expression of the chemokine receptors CCR2 [53] and CCR5 [54], further helping to immobilize TAMs. Hypoxia also induces a profound change in the phenotype of macrophages, promoting increased expression of a wide range of genes. This is brought about by the hypoxic up-regulation of such transcription factors as hypoxia-inducible factors, HIF-1␣ and HIF2␣. It has been reported that HIF-1␣ and HIF-2␣ are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumours [55,56]. TAMs respond to hypoxia by up-regulating a broad array of genes encoding proteins that promote the proliferation, invasion, and metastasis of tumour cells as well as tumour angiogenesis. Genes coding for M-CSF, a growth factor that promotes the survival and differentiation of macrophages [57], is over expressed in some human tumours, and elevated M-CSF levels correlate with high TAM numbers and poor prognosis [58]. Tumour cell mitogens such as fibroblast growth factor 2 (FGF2), platelet-derived growth factor, placental growth factor, and hepatocyte growth factor [59] were also shown to be up-regulated by macrophages in the in vitro system, when subjected to hypoxia. TAMs are also an important source of epidermal growth factor (EGF) [60] and VEGF [61] in human breast tumours. Hypoxic macrophages are also likely to promote the invasive and/or metastatic behavior of tumour cells by releasing such proinvasive factors as macrophage inhibitory factor [62]. Macrophage inhibitory factor is known to modulate the activities of a number of cell types in tumours, including stimulation of tumour cell motility [63]. This may involve indirect effects such as macrophage inhibitory factor-stimulated release of matrix metalloproteinase 9, which in turn degrades components of the basement membrane and extracellular matrix, thereby increasing the motility of tumour cells [64]. When macrophages are cocultured with tumour cells in the presence of endothelins 1 and 2 (cytokines that are themselves up-regulated in hypoxic tumour areas and known to have receptors on both macrophages and tumour cells), the secretion of MMP-2 and MMP-9 by tumour cells was increased, stimulating the invasive behavior of tumour cells [65].

5. Therapeutic interventions with natural products Three major aspects of TAMs, potentially amenable of therapeutic interventions are: (i) inhibition of their recruitment and/or of their survival at the tumour site; (ii) inhibition of their positive effects on angiogenesis and tissue remodelling; (iii) reversal of their immune-suppression and restoration of anti-tumour cytotoxicity. Anti-tumour agents with selective cytotoxic activity on monocyte–macrophages would be ideal therapeutic tools for their combined action on tumour cells and TAMs. Trabectedin, a natural product derived from the marine organism Ecteinascidia turbinata, with potent anti-tumour activity [66] is specifically cytotoxic in vitro to human macrophages and TAMs, while sparing the lymphocyte subset. In addition, at sub-cytotoxic concentrations trabectedin inhibits the production of CCL2 and IL-6 both by TAMs and tumour cells [67]. These anti-inflammatory properties of trabectedin may well contribute to its anti-tumour activity and deserves further investigation. In vivo administration of an alcoholic extract of Tinospora cordifolia was shown to up-regulate anti-tumour activity of tumour

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associated macrophages. The extract enhanced the differentiation of TAMs to dendritic cells in response to granulocyte/macrophagecolony stimulating factor, interleukin-4, and tumour necrosis factor. The dentritic cells showed an enhanced tumour cytotoxicity and production of tumouricidal soluble molecules like TNF, IL-1, and NO [68]. Abrus agglutinin, a plant lectin, in its native and heatdenatured forms activated the TAMs in Dalton’s lymphoma-bearing mice, which showed significantly increased in vitro cytotoxicity towards tumour cells and production of nitric oxide [69]. Studies in our laboratory have proved the ability of the methanolic extract of Biophytum sensitivum as well as amentoflavone, a biflavonoid from B. sensitivum, to inhibit the production of proinflammatory cytokines such as IL-1␤, IL-6, GM-CSF, TNF-␣ and nitric oxide (NO) by TAMs [70,71]. Rutin suppressed the expression and production of VEGF and IL-1␤ and stimulated the production of TNF-␣ by TAMs [72]. Paclitaxel (Taxol), a plant-derived diterpenoid, has effects on macrophages that are independent of the cell cycle. Paclitaxel induces normal host macrophage responses similar to those generated by bacterial lipopolysaccharide (LPS) [73] including enhanced NO [74], TNF-␣ [75], IL-1␤ [76] and superoxide anion [77] production and induction of NF-␬B expression [78]. Through increased NO and TNF-␣ production, paclitaxel enhances in vitro tumour cell cytotoxicity [74]. Moreover, Mullins et al. [79] demonstrated that paclitaxel restored IL-12 production by macrophages in tumourbearing mice. TAMs produce several matrix metalloproteases which degrade proteins of the extracellular matrix and also produce activators of MMPs, such as chemokines. In cervical cancer, biphosphonate zoledronic acid, a prototipical MMP inhibitor could suppress MMP-9 expression by infiltrating macrophages and thus block metalloprotease activity, reducing angiogenesis and cervical carcinogenesis [80]. Linomide, an anti-angiogenic agent, caused significant reduction of the tumour volume by inhibiting both recruitment and the stimulatory effects of TAMs on tumour angiogenesis without eliminating their anti-angiogenic effects in a murine prostate cancer model [81]. Linomide may thus prove to be more effective against prostate cancer. Chen et al. found that TAM density in non-small cell lung cancer surgical specimens correlated positively with tumour IL-8 mRNA expression and intratumour microvessel counts and negatively with patient survival. In addition, interaction between TAMs and several cancer cell/macrophage co-cultures (NSCLC cell line A549, lung adenocarcinoma cell lines CL1-0 and PC14, an osteogenic sarcoma cell line Saos2, and the HepG2 hepatoma cell line) resulted in marked up-regulation of IL-8 mRNA in lung cancer cells (270-fold) and, to a lesser degree, in macrophages (4.5fold). The increase in IL-8 mRNA expression correlated with the in vitro metastatic potential of the cancer cells. Anti-inflammatory agents such as pentoxifylline, celecoxib, pyrrolidine dithiocarbamate and dexamethasone suppressed induction of IL-8 mRNA expression in lung cancer cells in a dose dependent manner [82]. The presence of TAMs in glioma tissues was accompanied by increased expression of IL-8 mRNA and increased intratumour microvessel counts in paraffin-embedded surgical specimens of primary glioma patients. Similarly IL-8, IL-6 and RANTES proteins (regulated upon activation normal T-cell expressed and secreted) were also up-regulated in GBM8401 glioma cells after co-culture with human THP-1-derived macrophages. These findings imply that TAMs play an important role in promoting glioma growth and angiogenesis by inducing IL-8 expression in glioma cells via inflammatory stimuli or the nuclear factor kappa B pathway. The

increase in IL-8 expression was suppressed by anti-inflammatory agents such as pyrrolidine dithiocarbamate, pentoxifylline and dexamethasone [83]. Treatment with clodronate encapsulated in liposomes (clodrolip) efficiently depleted the level of TAM in the murine F9 teratocarcinoma and human A673 rhabdomyosarcoma mouse tumour models resulting in significant inhibition of tumour growth ranging from 75 to 92%. Tumour inhibition was accompanied by a drastic reduction in blood vessel density in the tumour tissue [84]. The strongest effects were observed with the combination therapy of clodrolip and an anti-VEGF single chain fragment antibodies, whereas free clodronate was not significantly active. In a different experimental model, the chemokine CCL5 was shown to be key in the recruitment of TAMs, and an antagonist, Met-CCL5, of this chemokine reduced the tumour infiltrate and slowed tumour growth [85].

6. TAMs and prognosis The cytokine profiles of microenvironment and localization of TAMs may influence the function of TAMs and thereafter the prognostic value of TAMs. The presence of extensive TAM infiltration has been shown to correlate with poor prognosis in carcinomas of the breast, cervix, and bladder, there is conflicting evidence for their role in prostate, lung and brain tumours. Lissbrant et al. [86] linked the volume density of TAMs to a shorter survival time in prostate carcinoma, while Shimura et al. [87] reported high TAM number to be an independent predictor of disease-free survival after surgery for this disease. Kerr et al. [88], when studying non-small cell lung carcinoma (NSCLC), which they considered to be histologically similar to regressing malignant melanoma, found a significant and positive correlation between tumour regression and high TAM number in close proximity to tumour cells. The relation between TAM density and the density of microvessels, and the influence of TAM density on prognosis were investigated in a clinical study with 113 pulmonary adenocarcinoma patients. A significant reduction in patient survival rate was detected in tumours with a high TAM density [89]. This indicates that TAM infiltration may contribute to tumour angiogenesis, and that TAM density may be taken as a useful prognostic marker in pulmonary adenocarcinoma. Bolat et al. [90] studied the correlations between microvessel density (MVD), VEGF expression, and TAMs and their relations to clinicopathological parameters such as tumour size, metastatic lymph node, mitotic activity index (MAI) and tumour grade in 48 cases of infiltrative ductal carcinoma (IDC). MVD showed a significant positive correlation with TAMs, VEGF, metastatic lymph nodes, tumour size and grade in IDC. These findings are suggestive of MVD and TAMs as an important prognostic factors in IDCs. Similarly a significant association between tumour size and stage, intratumoural microvessel density (MVD), VEGF-A expression and TAM count was seen in mucoepidermoid carcinoma patients [91]. Studies in patients with hepatocellular carcinoma showed that marginal macrophage density, but not intratumoural macrophage density, is associated with vascular invasion, tumour multiplicity and fibrous capsule formation [92]. Also there was a significant correlation between the density of TAMs and poor prognosis in those patients. Hansen et al. [93] suggested that presence of high numbers of tumour associated CD64+ macrophages in tumour biopsies before treatment significantly correlated negatively with the clinical outcome in patients with metastatic melanoma undergoing IL-2 based immunotherapy.

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7. Conclusion Though the presence of TAMs has long been considered as evidence for a host response against the growing tumour, it has become increasingly clear that TAMs are active players in the process of tumour progression and invasion. Molecular and biological studies have been supported by a large number of clinical studies that have found a significant correlation between the high macrophage content of tumours and poor patient prognosis. Over the past few years, understanding of the molecular mechanisms underlying recruitment and function of TAM has improved considerably. Treatments to decrease the number of TAMs in the tumour stroma will effectively alter the tumour microenvironment involved in tumour angiogenesis and progression, there by leading to markedly suppress tumour growth and metastasis. A better understanding of the regulation and function of TAMs may help to establish more therapeutically efficacious novel therapies for cancer management.

Acknowledgement The authors are thankful to Dr. Ramadasan Kuttan, Research Director, Amala Cancer Research Centre, for his kind support.

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