Mononuclear phagocyte heterogeneity in cancer: Different subsets and activation states reaching out at the tumor site

Abstract

Mononuclear phagocytes are amongst the most versatile cells of the body, contributing to tissue genesis and homeostasis and safeguarding the balance between pro- and anti-inflammatory reactions. Accordingly, these cells are notoriously heterogeneous, functioning in distinct differentiation forms (monocytes, MDSC, macrophages, DC) and adopting different activation states in response to a changing microenvironment. Accumulating evidence exists that mononuclear phagocytes contribute to all phases of the cancer process. These cells orchestrate the inflammatory events during de novo carcinogenesis, participate in tumor immunosurveillance, and contribute to the progression of established tumors. At the tumor site, cells such as tumor-associated macrophages (TAM) are confronted with different tumor microenvironments, leading to TAM subsets with specialized functions. A better refinement of the molecular and functional heterogeneity of tumor-associated mononuclear phagocytes might pave the way for novel cancer therapies that directly target these tumor-supporting cells.

Introduction

For a long time, the main focus in cancer research was centered on discovering the activating (oncogenes) or deactivating (tumor suppressor genes) mutations that drive the transformation of cells. Consequently, the development of cancer therapeutics was mainly a search for ways to interfere with cancer cell-intrinsic characteristics. By now, it is clear that tumors should be considered as organ-like structures in which a complex bidirectional interplay exists between transformed and non-transformed cells. These unmutated tumor-associated cells include cells of the innate and adaptive immune system, and represent valid targets for therapy. As a matter of fact, immune cells, in particular cells belonging to the mononuclear phagocyte system (including lineage committed bone marrow precursors, monocytes, and macrophages), are reported to take part in every aspect of a tumor's natural history, from tumor initiation and immunoediting to primary tumor growth and metastasis. Indeed, macrophages are central orchestrators of some of the chronic inflammatory diseases predisposing to cancer, such as Helicobacter pylori-driven gastric carcinoma (Kaparakis et al. 2008), colitis-associated colon carcinoma (Grip et al. 2003) and hepatitis-mediated hepatocellular carcinoma (Heymann et al. 2009). Within the context of an established tumor, the normal physiological functions of monocytes and macrophages are often (with some notable exceptions) harnessed in favor of tumor progression, resulting in survival and stimulation of cancer cell proliferation, promotion of cancer cell motility, invasiveness and intravasation, angiogenesis, immunosuppression and extracellular matrix reorganization (Mantovani et al., 1992, Mantovani et al., 2002, Qian and Pollard, 2010). The tumor microenvironment is fundamentally different from sites of chronic inflammation and so is the macrophage phenotype in these distinct regions, reflecting the remarkable adaptability of these cells to a changing environment. The most often used terms in phenotyping macrophages are classically activated macrophages (or M1), elicited by a type I cytokine environment and/or recognition of pathogen-associated molecular patterns or endogenous danger signals, and alternatively activated macrophages (or M2) elicited in a type II cytokine environment (Goerdt and Orfanos, 1999, Mantovani et al., 2004, Van Ginderachter et al., 2006b). Though a useful working scheme, it should be realized that any form of classification underscores the complexity of the in vivo situation, where macrophages are exposed to a mixture of stimuli and will adopt mixed functional profiles accordingly. This is exemplified by the determination of a consensus gene signature for in vivo induced M2 in different pathologies, which not only contains genes that are strictly IL-4/IL-13-inducible such as E-cadherin (Van den Bossche et al. 2009), but equally so genes that are not inducible in vitro by any of the known M2 inducing stimuli (Hassanzadeh Ghassabeh et al. 2006). This heterogeneity is at the heart of the macrophage's polyvalency, making them indispensable for functions as diverse as development and tissue homeostasis (trophic macrophages), pathogen clearance, Th1 or Th2 cytokine-driven inflammation (reflected by the classical versus alternative model of macrophage activation), and wound healing (Gordon and Taylor, 2005, Mosser and Edwards, 2008).