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Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms¹

Subhra K. Biswas^*, Antonio Sica and Claire E. Lewis^2,

^* Singapore Immunology Network, Biomedical Sciences Institutes, Agency for Science, Technology and Research, Singapore; Istituto Clinico Humanitas, Rozzano, Milan, Italy; Tumor Targeting Group, Academic Unit of Pathology, The Sir Henry Wellcome Laboratories for Medical Research, University of Sheffield Medical School, Sheffield, United Kingdom

Recent studies have shown that macrophages play an important part in both tumor initiation and various key steps in growth and metastasis. These cells show a remarkable degree of plasticity during tumor development with a "switch" in macrophage phenotypes occurring during the course of tumor progression. During chronic inflammation they appear to predispose a given tissue to tumor initiation by the release of factors that promote neoplastic transformation. Following this, their phenotype shifts more toward one that is immunosuppressive and supports tumor growth, angiogenesis, and metastasis. In this review, we discuss the evidence for this plasticity of macrophage functions, the specific signaling mechanisms that may be regulating it, and the new targets for anticancer therapies highlighted by these findings.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ S.K.B. acknowledges funding from Biomedical Research Council, Agency for Science Technology and Research, Singapore. A.S. is supported by grants from Italian Ministry of Health, Italian Association for Cancer Research, and European Community. C.E.L. gratefully acknowledges the support of the Breast Cancer Campaign and Yorkshire Cancer Research for the work of her group in this area.

² Address correspondence and reprint requests to Dr. Claire E. Lewis, ³Tumor Targeting Group, Academic Unit of Pathology, The Sir Henry Wellcome Laboratories for Medical Research, University of Sheffield Medical School, Sheffield S10 2RX, U.K. E-mail address: claire.lewis{at}sheffield.ac.uk

³ Abbreviations used in this paper: RNI, reactive nitrogen intermediate; Ang, angiopoietin; ApoE, apolipoprotein E; DEN, diethylnitrosamine; HA, hyaluronan; HCC, hepatocellular carcinoma; IKK, inhibitor of B kinase; iNOS, inducible NO synthase; IRF, IFN regulatory factor; ROI, reactive oxygen intermediate; TAM, tumor-associated macrophage; TBK, TANK-binding kinase; TRIF, TLR/IL-1R domain-containing adaptor inducing IFN-β; VEGF, vascular endothelial growth factor.