Review
Differentiation and gene expression profile of tumor-associated macrophages

https://doi.org/10.1016/j.semcancer.2012.02.002Get rights and content

Abstract

Tumor microenvironment is composed of proliferating neoplastic cells, a vascular network of endothelial cells, extra cellular matrix produced by fibroblasts, cellular compartments of adaptive immunity like lymphocytes and dendritic cells as well as cells of innate immunity, e.g., natural killer cells and macrophages. Many pre-clinical and clinical studies demonstrate an inversed correlation between macrophage infiltrate and patients’ prognosis indicating a macrophage supporting role for tumor progression as producers of growth and angiogenic factors and as regulators of tissue remodelling. Based on in vitro models, macrophages have been classified in pro-inflammatory, classically activated macrophages (M1; stimulated by IFN-γ or LPS) and anti-inflammatory, alternatively activated macrophages (M2; stimulated by either IL-4/IL-13, IL-1β/LPS in combination with immune complexes or by IL-10/TGFβ/glucocorticoids). Tumor escape has been linked with a switch from M1 activation in the early tumor initiation process towards M2-like phenotype during tumor progression, a process that highlights the heterogeneity and plasticity of macrophage activation and which offers a possible therapeutic target directed against reversing the TAM phenotype in the tumor. Here, we review different tumor-environmental stimuli and signalling cascades involved in this switch in differentiation and the so connected gene regulation in TAMs. In addition, therapeutic applications deducted from this differentiation and gene regulatory processes are presented. Data from pre-clinical as well as clinical studies clearly support the notion, that TAMs are excellent novel therapeutic targets for the fight against cancer.

Introduction

Solid tumors can be compared to organ-like structures composed of malignant, haematopoietic and mesenchymal cells, which permanently interact and influence each other. In the past, research focused mainly on the genetically compromised tumor cells themselves, in the last decade the interest shifted towards other cells of the tumor-microenvironment as their prominent role in tumor initiation, development and metastasis became more and more evident [1]. Although crosstalk between cells composing the tumor-microenvironment can strongly support tumor evolvement, it also bears the potential to modulate tumor biology, which creates novel possibilities for therapeutic interventions in the fight against cancer. A prerequisite therefore is a solid knowledge of pathophysiological processes present in the diverse tumor settings. Different cell types have advanced in the center of attention of researchers as stem cells, fibroblasts, leukocytes or endothelial cells [2]. In this review the main focus will be set on a central player in tumorbiology: the tumor-associated macrophage (TAM).

Section snippets

Classification of macrophages

Macrophages belong to the mononuclear phagocytic system, which includes monocytes, macrophages and dendritc cells. They were first described by Elie Metchnikoff as phagocytic cells present in vertebrates and invertebrates with bactericidal abilities. Thereafter, research focused for a long time on pro-inflammatory actions of macrophages disregarding their key functions in regulating de-escalation of inflammation and their importance in keeping up a homeostatic environment in the body. Only in

Transcriptional regulation of macrophage differentiation

Macrophages are easy to generate from bone-marrow precursors in vitro by stimulation with M-CSF or GM-CSF and can be further directed into definitive macrophage sub-classes by external stimuli like cytokines and other mediators.

For myeloid differentiation the transcription of Runt-related transcription factor 1 (RUNX1) target genes are essential. One of these target genes encompasses the transcription factor PU.1 [12]. For macrophage differentiation, PU.1 functions as a transcription factor but

Differentiation of TAMs in tumor initiation and tumor progression

A pathophysiological association between inflammation and cancer has already been proposed in the nineteenth century by the German pathologist Rudolf Virchow [26]. He suggested that chronic irritation induced by chronic inflammation might trigger cancer initiation. 90–95% of neoplasias are linked to obesity, tobacco smoke, environmental pollutants, radiation and chronic infections, which all have in common a chronic inflammatory state [26]. Macrophages constitute a significant part of the

Role of expressed genes in TAM

During macrophage differentiation in the tumor microenvironment diverse signalling cascades as mentioned above converge to induce a special gene expression profile characteristic for TAMs. Many of these genes are involved in functional processes important for tumor progression as immuno-regulation, angiogenesis and matrix remodelling and include secreted cytokines, chemokines, functional enzymes and surface molecules.

Targeting TAMs as an effective anti-cancer therapy

This review highlights the clinical relevance of macrophages for tumor initiation and progression, which qualifies them as a potential therapeutic target. Targeting inflammation in general has already been proven to work as a prophylactic method to prevent tumor incidence and progression by regular intake of non-steroidal anti-inflammatory drugs (NSAID) [102]. In an experimental colorectal cancer model, chemopreventive effects of NSAID were found to be mediated by their inhibitory effects on

Conflict of interest

None.

Acknowledgement

This work was supported in part by grants of Deutsche Forschungsgemeinschaft SFB938, project H to S.G. We thank Amanda Mickley for critical proofreading of the manuscript.

References (120)

  • B. Zhang et al.

    M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma

    Clinics (Sao Paulo)

    (2011)
  • T. Fujiwara et al.

    Macrophage infiltration predicts a poor prognosis for human ewing sarcoma

    Am J Pathol

    (2011)
  • A. Mantovani et al.

    Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors

    Semin Cancer Biol

    (2004)
  • A. Sparmann et al.

    Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis

    Cancer Cell

    (2004)
  • J.F. Bromberg et al.

    Stat3 as an oncogene

    Cell

    (1999)
  • F.R. Greten et al.

    IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer

    Cell

    (2004)
  • B.J. Nickoloff et al.

    Inflammation and cancer: is the link as simple as we think

    J Invest Dermatol

    (2005)
  • K. Chen et al.

    Toll-like receptors in inflammation, infection and cancer

    Int Immunopharmacol

    (2007)
  • J.R. White et al.

    Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis

    Genomics

    (2004)
  • O.M. Pello et al.

    Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

    Blood

    (2012)
  • R. Kopan et al.

    The canonical Notch signaling pathway: unfolding the activation mechanism

    Cell

    (2009)
  • L. Sanchez-Martin et al.

    The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression

    Blood

    (2011)
  • A. Mantovani et al.

    The chemokine system in diverse forms of macrophage activation and polarization

    Trends Immunol.

    (2004)
  • S.K. Biswas et al.

    A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)

    Blood

    (2006)
  • P. Allavena et al.

    Chemokines in cancer related inflammation

    Exp Cell Res

    (2011)
  • M.J. Gray et al.

    Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta

    Gene

    (2005)
  • F. Pucci et al.

    A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood resident monocytes, and embryonic macrophages suggests common functions and developmental relationships

    Blood

    (2009)
  • M. De Palma et al.

    Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications

    Trends Immunol

    (2007)
  • S.D. Mason et al.

    Proteolytic networks in cancer

    Trends Cell Biol

    (2011)
  • G.O. Ahn et al.

    Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells

    Cancer Cell

    (2008)
  • R. Prevo et al.

    Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium

    J Biol Chem

    (2001)
  • H. Korkaya et al.

    Breast cancer stem cells, cytokine networks, and the tumor microenvironment

    J Clin Invest

    (2011)
  • P.A. Kenny et al.

    Targeting the tumor microenvironment

    Front Biosci

    (2007)
  • M. Stein et al.

    Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation

    J Exp Med

    (1992)
  • P. Hogger et al.

    Identification of the integral membrane protein RM3/1 on human monocytes as a glucocorticoid-inducible member of the scavenger receptor cysteine-rich family (CD163)

    J Immunol

    (1998)
  • V. Kodelja et al.

    Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern

    J Immunol

    (1998)
  • F.O. Martinez et al.

    Macrophage activation and polarization

    Front Biosci

    (2008)
  • D.M. Mosser et al.

    Exploring the full spectrum of macrophage activation

    Nat Rev Immunol

    (2008)
  • R.P. DeKoter et al.

    Regulation of B lymphocyte and macrophage development by graded expression of PU.1

    Science

    (2000)
  • T. Krausgruber et al.

    IRF5 promotes inflammatory macrophage polarization and TH1–TH17 responses

    Nat Immunol

    (2011)
  • T. Satoh et al.

    The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection

    Nat Immunol

    (2010)
  • F. De Santa et al.

    Jmjd3 contributes to the control of gene expression in LPS-activated macrophages

    EMBO J

    (2009)
  • T. Lawrence et al.

    Transcriptional regulation of macrophage polarization: enabling diversity with identity

    Nat Rev Immunol

    (2011)
  • J.E. Darnell et al.

    Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

    Science

    (1994)
  • K. Takeda et al.

    Essential role of Stat6 in IL-4 signalling

    Nature

    (1996)
  • B. Gorgoni et al.

    C/EBP beta gene inactivation causes both impaired and enhanced gene expression and inverse regulation of IL-12 p40 and p35 mRNAs in macrophages

    J Immunol

    (2002)
  • B.B. Aggarwal et al.

    Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe

    Clin Cancer Res

    (2009)
  • L.F. Porrata et al.

    Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in classical Hodgkin lymphoma

    Haematologica

    (2012)
  • M.A. Zaki et al.

    Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma

    Virchows Arch.

    (2011)
  • Y. Komohara et al.

    Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma

    Cancer Sci

    (2011)
  • Cited by (0)

    View full text