ReviewDifferentiation and gene expression profile of tumor-associated macrophages
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)
- et al.
Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway
Blood
(2006) - et al.
Evolutionary conservation of alternative activation of macrophages: structural and functional characterization of arginase 1 and 2 in carp (Cyprinus carpio L.)
Mol Immunol
(2006) - et al.
Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes
Blood
(2009) - et al.
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
Trends Immunol
(2002) - et al.
Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene
Cell
(1996) - et al.
Control of inducible gene expression by signal-dependent transcriptional elongation
Cell
(2009) - et al.
CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex
J Biol Chem
(2005) - et al.
A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling
Cell.
(2009) - et al.
PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties
Cell Metab
(2007) - et al.
Alternative activation of macrophages: mechanism and functions
Immunity
(2010)