ReviewMononuclear phagocyte heterogeneity in cancer: Different subsets and activation states reaching out at the tumor site
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).
Section snippets
Mononuclear phagocytes in tumor initiation
Epidemiological studies clearly established a causal link between chronic inflammation – triggered by microbial infections or autoimmune diseases – and tumor development. This was further confirmed by the chemopreventive effect of nonsteroidal anti-inflammatory drugs and ligands for the anti-inflammatory nuclear receptor PPARγ (Grivennikov et al., 2010, Karin et al., 2006, Coussens and Werb, 2002, Balkwill et al., 2005, Van Ginderachter et al., 2008). These correlative data have recently been
Mononuclear phagocytes in tumor immunosurveillance
The combination of mutagenic and epigenetic alterations in transformed cells has the potential to alert the immune system, possibly leading to the cancer cell's eradication. Accumulating evidence over the past years has provided a solid basis for this immunosurveillance theory. Indeed, mice with genetic deficiencies in various immune functions develop more readily tumors, be it spontaneously or upon treatment with carcinogens (Vesely et al. 2010). In colorectal cancer patients, and possibly
Heterogeneity of mononuclear phagocytes in established tumors
Most of the studies on the interplay between mononuclear phagocytes and cancer are performed on established tumors. Tumors function as complex organs, containing multiple interacting cell types and a multitude of specialized microenvironments instructing different characteristics on the cells present. This complexity is reflected by the heterogeneity of tumor-associated mononuclear phagocytes, both at the level of differentiation and activation. Distinguishing these different myeloid cell types
Concluding remarks
By now, sufficient evidence is available to proclaim tumor-associated mononuclear phagocytes as prime targets for therapeutic intervention. This is illustrated by succesful attempts to redirect tumor-infiltrating macrophages and dendritic cells towards tumor rejection (Guiducci et al., 2005, Stout et al., 2009) or by anticancer effects of TAM and TADC elimination (Luo et al., 2006, Song et al., 2009). Several new developments are expected to further expand the toolbox of TAM-directed anticancer
Acknowledgements
This work was supported by a “Stichting tegen Kanker” grant to J.V.G. and P.D.B.; by a doctoral grant from the Fund for Scientific Research Flanders (FWO-Vlaanderen) to E.V.O., K.M., and E.S.; by a doctoral grant from the “Institute for Promotion and Innovation by Science and Technology in Flanders” (IWT-Vlaanderen) to D.L., A.N. and Y.M. and by the “Fund for Scientific Research Flanders” (FWO-Vlaanderen).
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