The inflammatory micro-environment in tumor progression: The role of tumor-associated macrophages

doi:10.1016/j.critrevonc.2007.07.004

Critical Reviews in Oncology/Hematology

Volume 66, Issue 1, April 2008, Pages 1-9

https://doi.org/10.1016/j.critrevonc.2007.07.004 Get rights and content

Abstract

The link between inflammation and cancer proposed more than a century ago by Rudolf Virchow, who noticed the infiltration of leukocytes in malignant tissues, has recently found a number of genetic and molecular confirmations. Experimental, clinical and epidemiological studies have revealed that chronic inflammation contributes to cancer progression and even predisposes to different types of cancer. Cancer-associated inflammation includes: the presence of leukocyte infiltration; the expression of cytokines such as tumor necrosis factor (TNF) or interleukin (IL)-1; chemokines such as CCL2 and CXCL8; active tissue remodelling and neo-angiogenesis.

Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. Many observations indicate that, in the tumor micro-environment, TAM have several protumoral functions, including expression of growth factors, matrix proteases, promotion of angiogenesis and suppression of adaptive immunity. In this review we will discuss the role of TAM in the inflammatory micro-environment of solid tumors and will try to identify potential target for future therapeutic approaches.

Section snippets

Origin of TAM

Solid tumors are constituted by variable amounts of neoplastic and stromal cells, the latter comprising fibroblasts, blood/lymphatic vessels and immune-competent cells, mainly macrophages and lymphocytes. A wide array of biologically active molecules are available in this milieu, either in soluble form or associated to proteins of the extra-cellular matrix. These include, for instance, growth factors for tumor cells and for the newly formed blood vessels, chemoattractants for immune cells

Plasticity of human macrophages: M1 and M2 polarization

Monocytes recruited from the circulation differentiate into mature macrophages within the tumor micro-environment. The capability to express distinct functional programmes in response to different micro-environmental signals is a biological feature of macrophages, which is typically manifested in pathological conditions such as infections and cancer [18], [19], [20], [21], [22]. In response to cytokines and microbial products, mononuclear phagocytes express specialized functional properties.

TAM as M2 polarized macrophages

Micro-environmental signals expressed at the tumor micro-environment play a central role in the orientation and differentiation of recruited mononuclear phagocytes, thus contributing to hijack the local immune system away from anti-tumor functions. To the extent that they have been investigated, differentiated mature TAM have phenotype and functions more similar to M2 macrophages [28]. Indeed, under many aspects TAM summarize a number of functions expressed by M2 macrophages: tuning of

TAM as promoter of tumor progression

Earlier in vitro studies with IFNγ-stimulated macrophages or TAM had indicated that under certain conditions these cells display cytotoxic functions against tumor cells [7], [28]. However, it was already clear that in the absence of M1-orienting signals TAM rather promoted tumor cell growth in vitro, as well as in experimental murine models [5], [25], [28], [36], [37]. Since then, in many – but not all human tumors – a high frequency of infiltrating TAM has been associated with poor prognosis

Conclusions and therapeutic perspectives

TAM are key orchestrator of the link between smouldering inflammation and cancer progression. In the majority of experimental and clinical studies the evidence is a pro-tumoral function of TAM. Thus TAM appear as attractive candidate of novel therapeutic strategies. Three major aspects of TAM, potentially amenable of therapeutic interventions are: (i) inhibition of their recruitment and/or of their survival at the tumor site; (ii) inhibition of their positive effects on angiogenesis and tissue

Reviewers

1.
Patrick De Baetselier: [email protected].
2.
Karin de Visser: [email protected].
3.
Kouji Matsushima: [email protected].
4.
Vincenzo Bronte: [email protected].

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC); by grant Oncologia 2006 (Ministry of Health) Italy; and by the FP6 European Project ATTACK LSHC-CT-2005-018914.

Paola Allavena, M.D. leads the Laboratory of Cellular Immunology at the Department of Immunology and Inflammation, IRCCS Istituto Clinico Humanitas in Rozzano, Milan. She has extensive experience in tumor immunology, inflammation/innate immunity, monocytes–macrophages, chemokines and their receptors. She is author of more than 160 peer-reviewed scientific articles.

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Antonio Sica, Ph.D. leads the Laboratory of Molecular Immunology at the Department of Immunology and Inflammation, IRCCS Istituto Clinico Humanitas in Rozzano, Milan. He is expert in the transcription factors activated in tumor-associated macrophages and in hypoxia.

Graziella Solinas is a Ph.D. student at the IRCSS Istituto Clinico Humanitas, Laboratory of Cellular Immunology. She studies the tumor micro-environment and in particular the differentiation of macrophages as important components potentially favouring tumor progression.

Chiara Porta, Ph.D. is a post-doc at the IRCSS Istituto Clinico Humanitas, Laboratory of Molecular Immunology. She studies the molecular mechanisms underlying the pro-tumoral functions of tumor macrophages.

Alberto Mantovani, M.D. is the scientific director of the IRCCS Istituto Clinico Humanitas (Rozzano-Milan, Italy) and full professor of general pathology at the University of Milan. Prof. Mantovani's main interests are innate immunity/inflammation, macrophages, tumors, cytokines, chemokines, Toll-like receptors, pentraxins. He is author of more than 300 peer-reviewed scientific articles.

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The inflammatory micro-environment in tumor progression: The role of tumor-associated macrophages

Abstract

Section snippets

Origin of TAM

Plasticity of human macrophages: M1 and M2 polarization

TAM as M2 polarized macrophages

TAM as promoter of tumor progression

Conclusions and therapeutic perspectives

Reviewers

Conflict of interest

Acknowledgments

Lancet

Cancer Cell

Eur J Cancer

Immunol Today

Semin Cancer Biol

Immunity

Trends Immunol

Immunity

Trends Parasitol

Immunobiology

Trends Immunol

Trends Immunol

Am J Pathol

Eur J Cancer

Cell

Cancer Cell

Am J Pathol

J Biol Chem

Semin Cancer Biol

J Biol Chem

Am J Pathol

Blood

Cell

Cell

Immunobiology

J Biol Chem

Blood

Semin Cancer Biol

Trends Immunol

Inflammation and cancer

Nature

The role of tumor-associated macrophages in tumor progression: implications for new anticancer therapies

J Pathol

Tumor-educated macrophages promote tumor progression and metastasis

Nat Rev Cancer

Regulation of the macrophage content of neoplasms by chemoattractants

Science

Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line

J Exp Med

Chemokines and cancer

Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines

Cancer Immunol Immunother

Cancer and the chemokine network

Nat Rev Cancer

The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer

J Clin Invest

Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer

Clin Cancer Res

Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in non-tumorigenic melanoma cells

J Immunol

The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity

Cancer Res

Alternative activation of macrophages

Nat Rev Immunol

Monocyte and macrophage heterogeneity

Nat Rev Immunol

Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria

Proc Natl Acad Sci USA

Blocking IL-1 in systemic inflammation

J Exp Med

The many faces of macrophage activation

J Leukoc Biol

Interleukin-10 prevents the differentation of monocytes to dendritic cells but promotes their maturation to macrophages

Eur J Immunol