Review Tumor-associated macrophages: Effectors of angiogenesis and tumor progression Seth B. Coffelt, Russell Hughes, Claire E. Lewis ⁎ Academic Unit of Pathology, Medical School, University of Sheffield, Sheffield, S10 2RX, UK abstract article info Article history: Received 22 December 2008 Received in revised form 6 February 2009 Accepted 18 February 2009 Available online 6 March 2009 Keywords: Myeloid cells Macrophage Tumor Angiogenesis Lymphangiogenesis Immunosuppression Metastasis Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population in many tumor types residing in both perivascular and avascular, hypoxic regions of these tissues. Analysis of TAMs in human tumor biopsies has shown that they express a variety of tumor-promoting factors and evidence from transgenic murine tumor models has provided unequivocal evidence for the importance of these cells in driving angiogenesis, lymphangiogenesis, immunosuppression, and metastasis. This review will summarize the mechanisms by which monocytes are recruited into tumors, their myriad, tumor-promoting functions within tumors, and the influence of the tumor microenvironment in driving these activities. We also discuss recent attempts to both target/destroy TAMs and exploit them as delivery vehicles for anti-cancer gene therapy. © 2009 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2. Mechanisms of monocyte recruitment to tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3. Contribution of TAMs to tumor development and progression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.1. Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.2. Lymphangiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3. Invasion and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.4. Immune evasion and suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4. Role of TAMs in tumor recovery after therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.1. Regulation of TAM function by the tumor microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 5. Therapeutic implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 1. Introduction For over a hundred years, oncologists and cancer researchers have reported that solid tumors consist of both malignant cells and a number of stromal cell types [1]. While the tumor cell population has understandably received most attention, recent studies have shown that cells in the stromal compartment are a dynamic, flexible asset to tumor development, reorganizing and evolving in response to cues from malignant cells as the tumor advances [2]. Among the stromal cell subsets, one particular inflammatory cell, the macrophage, has gained considerable attention recently due to evidence demonstrating a pivotal role for these cells in promoting tumor neovascularization and progression. Macrophages are a highly versatile and multifunctional compo- nent of the innate immune system that differentiate in tissues from extravasating monocytes (Fig. 1). Monocytes and macrophages belong to the myeloid lineage of leukocytes and, as such, originate from the same progenitor cells in the bone marrow as neutrophils, eosinophils, and mast cells, among others. Macrophages are characterized by a distinct subset of cell surface markers, their ability to engulf invading microbes or cell debris from injured sites, secrete a wide array of immunomodulatory cytokines, present antigens to T cells, and act as accessory cells in lymphocyte activation [3]. These cells play a critical role in the emergence and resolution of inflammation and in the maintenance of tissue homeostasis through remodeling and repair. Biochimica et Biophysica Acta 1796 (2009) 11–18 ⁎ Corresponding author. E-mail address: Claire.lewis@sheffield.ac.uk (C.E. Lewis). 0304-419X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2009.02.004 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbacan