Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression
Introduction
It has long been recognised that leucocytes infiltrate neoplastic tissues [29]. Cells belonging to the monocyte-macrophages lineage are a major component of the leucocyte infiltrate of neoplasms. Tumour-associated macrophages (TAM) originate from circulating blood monocytes. Their recruitment and survival in situ is directed by chemokines [29] and by cytokines which interact with tyrosine kinase receptors. TAM have complex dual functions in their interaction with neoplastic cells (the “macrophage balance” hypothesis [29], but strong evidence suggests that they are part of inflammatory circuits that promote tumour progression [5], [29].
It was in 1863 that Rudolf Virchow noted leucocytes in neoplastic tissues and made a connection between inflammation and cancer. He suggested that the “lymphoreticular infiltrate” reflected the origin of cancer at sites of chronic inflammation. Over the past ten years, our understanding of the inflammatory microenvironment of malignant tissues has supported Virchow's hypothesis, and the links between cancer and inflammation are starting to have implications for prevention and treatment. Here, we will review evidence consistent with the view that TAM are a polarised type II macrophage population. Polarised type II (or M2 or alternatively activated macrophages) are oriented to angiogenesis, tissue remodelling and repair. We propose that the neoplastic tissue represents a Darwinian microenvironment which selects for macrophage properties that are favourable, for tumour growth and progression.
Section snippets
Macrophage plasticity
Macrophages are versatile, plastic cells, which respond to environmental signals with diverse functional programmes. Classic macrophage activation in response to microbial products and interferon-γ (IFN-γ) has long been recognised. More recently, it was realised that anti-inflammatory molecules, such as glucocorticoid hormones, interleukin-4 (IL-4), IL-13 IL-10, are more than simple inhibitors of macrophage activation, in that they induce a distinct activation programme (alternatively activated
Recruitment, survival and differentiation of TAM
TAM derive from circulating monocytic precursors and in situ proliferation is generally not an important mechanism that sustains the mononuclear phagocyte population, at least in human tumours [29]. Several lines of evidence, including correlation between production and infiltration in murine and human tumours, passive immunisation and gene modification, indicate that chemokines play a pivotal role in the recruitment of monocytes in neoplastic tissues [41]. Indeed, tumours have been invaluable
Modulation of adaptive immunity by TAM
It has long been known that TAM have poor antigen presenting capacity and can actually suppress T cell activation and proliferation [5]. The suppressive mediators produced by TAM include prostaglandins, IL-10 and TGFβ [47]. Moreover, they do not produce IL-12 spontaneously and they are refractory to stimulation by IFNγ and lipopolysaccharide (LPS). The IL-10high IL-12low phenotype is characteristic of polarised type II macrophages (see above). Antibody blocking experiments suggest that
Tissue repair and angiogenesis
Phagocytes play a central role in tissue remodelling and repair during oncogenesis and adult life. This ancestral function of mononuclear phagocytes is expressed by TAM which orchestrate the function of other components of the tumour stroma. TAM produce a host of growth factors which affect tumour cell proliferation, angiogenesis, and the deposition and dissolution of connective tissues. These include epidermal growth factor (EGF), members of the fibroblast growth factor (FGF) family, TGFβ,
Hypoxia and TAM
Uneven vascularisation and hypoxia are characteristics of neoplastic tissues which affect macrophage distribution and function. TAM accumulate preferentially in the poorly vascularised region of tumours which are characterised by low oxygen tension. Macrophage migration is suppressed in hypoxic conditions [16] and TAM are immobilised in avascular [27] and necrotic hypoxic areas of tumours [28]. Evidence suggests that in hypoxic conditions, TAM are stimulated to co-operate with tumour cells and
Therapeutic intervention
Having established the protumoural activity of TAM, possible strategies that involve these cells should include reducing the number of host macrophages and/or increasing their tumouricidal activity. Reduction of macrophages has indeed been associated with tumour inhibition [25], [37]. We and other groups have observed that TAM are committed to high production of the inhibitory cytokine IL-10 [47], which mediates defective IL-12 production and NF-κB activation in tumour-associated macrophages.
Concluding remarks
The available information suggests that TAM are a prototypic, polarised type II mononuclear phagocyte population (Fig. 1). We are aware that the view of TAM as a skewed type II macrophage population is problably an oversimplification. Yet, the view of TAM as a polarised M2 macrophage is efficacious in summarising the current understanding of the immunobiology of these cells.
As polarised type II macrophages, TAM participate in circuits that regulate tumour growth and progression, adaptive
Acknowledgements
This work was supported by MIUR (Ministero Istruzione Universitá e Ricerca), FIRB Projects No. RBAU01PTYW to Antonio Sica and RBNE01Y3N3 to Alberto Mantovani and by AIRC (Italian Association for Cancer Research).
References (55)
- et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001) - et al.
MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis
Cell
(2000) - et al.
HIF-1α is essential for myeloid cell-mediated inflammation
Cell
(2003) - et al.
Vascular endothelial growth factor-165 overexpression stimulates angiogenesis and induces cyst formation and macrophage infiltration in human ovarian cancer xenografts
Am. J. Pathol.
(2002) - et al.
The origin and function of tumor-associated macrophages
Immunol. Today
(1992) The chemokine system: redundancy for robust outputs
Immunol. Today
(1999)- et al.
Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines
Trends Immunol.
(2001) - et al.
Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphoangiogenesis
Am. J. Pathol.
(2002) - et al.
Identification of biologically active chemokine isoforms from ascitic fluid and elevated levels of CCL18/pulmonary and activation-regulated chemokine in ovarian carcinoma
J. Biol. Chem.
(2002) - et al.
The expression and distribution of the hypoxia-inducible factors HIF- 1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages
Am. J. Pathol.
(2000)
High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin's lymphoma
Am. J. Pathol.
Papillary carcinoma of the thyroid: hepatocyte growth factor (HGF) stimulates tumor cell to release chemokines active in recruiting dendritic cells
Am J Pathol
Placental growth factor is a survival factor for tumor endothelial cells and macrophages
Cancer Res.
The chemokine receptor switch paradigm and dendritic cell migration: its significance in tumor tissues
Immunol. Rev.
Cytoçoxic effector cell function at different stages of human monocyte-macrophage maturation
Cancer Res.
The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity
Cancer Res.
Tumor-induced immune dysfunctions caused by myeloid suppressor cells
J. Immunother.
Inflammation and cancer
Nature
Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors
J. Leukoc. Biol.
Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages
Oncogene
The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduced expression of the inducible nitric oxide synthase gene
J. Exp. Med.
Alternative activation of macrophages
Nat. Rev. Immunol.
Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation – a potential mechanism
Eur. J. Immunol.
The tumorigenie and angiogenic effects of MGSA/GRO proteins in melanoma
J. Leukoc. Biol.
Macrophages from cancer patients: analysis of TRAIL, TRAIL receptors, and colon tumor cell apoptosis
J. Natl. Cancer Inst.
Mechanisms by which tumor cells and monocytes expressing the angiogenic factor thymidine phosphorilase mediate human endothelial cell migration
Cancer Res.
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