Various epidemiological, clinical and experimental studies have not only demonstrated a link between chronic inflammation and cancer onset but also shown that inflammatory mediators such as myeloid cells significantly contribute to tumour progression 1,2 . As discussed in detail elsewhere in this issue, tumour angiogenesis is a crucial step in tumour development as tumours have to establish a blood supply in order to grow and metastasize. Although tumour cells were first thought to drive the cellular events underpinning tumour angiogenesis, considerable evidence has now emerged for the central role of tumour-infiltrating mye- loid cells such as monocyte/macrophages, neutrophils, eosinophils, mast cells (MC) and dendritic cells (DC) in this phenomenon. This Review focuses on the multifaceted ability of each of these cell types to promote tumour angiogenesis and the way in which these pro-tumour functions are activated and modulated by the tumour microenvironment. The pos- sible role in tumour angiogenesis of other bone marrow- derived cells, such as platelets, endothelial progenitor cells and haematopoietic stem cells, has been discussed in detail elsewhere 3–5 and will not be included here. Macrophages These highly versatile, multifunctional cells are charac- terized by their ability to engulf invading microbes or cell debris from injured sites, secrete a wide array of immu- nomodulatory cytokines, present antigens to T cells and act as accessory cells in lymphocyte activation. They dis- play a high degree of plasticity, altering their phenotype to suit the microenvironment in which they reside. The conventional understanding is that macrophages can be subdivided into M1 (classically activated) or M2 (alternatively activated) phenotypes (FIG. 1). M1 macro- phages exhibit a pro-inflammatory phenotype and are activated by lipopolysaccharide and interferon γ (IFNγ) to secrete bactericidal factors and promote T-helper-1 (T H 1) responses. By contrast, M2 macrophages have an immunosuppressive phenotype and release cytokines that promote a T H 2 response 6 . Macrophages in tumours — usually termed tumour- associated macrophages (TAM) — often express many genes typical of the M2 phenotype 7,8 and have therefore been described as ‘M2-skewed’. However, recent evidence has suggested that the phenotype of TAM varies with the stage of tumour development, with M1-like cells often predominating at sites of chronic inflammation where tumours can develop, then switching to an M2-like phenotype as the tumour begins to invade, vascularize and develop 9 . There are usually higher numbers of TAM in malig- nant tumours than surrounding normal tissues 10 . These cells initially extravasate across the tumour vasculature as monocytes from the blood, starting to differentiate into TAM as they do so 11 . Monocyte recruitment is driven by chemoattractants secreted by both malignant and stro- mal cells in tumours (reviewed in REF. 12). The main one is chemokine CCL2 (MCP-1; see BOX 1), the expression of which is usually increased in tumours 13–15 . Increased levels of other monocyte-attracting chemokines such as placental growth factor (PlGF, PGF) 16 , CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) have also been described in tumours 17 . The potent pro-angiogenic factor *Department of Oral and Maxillofacial Surgery, School of Clinical Dentistry and ‡ Academic Unit of Pathology, Medical School, Beech Hill Road, University of Sheffield, Sheffield, UK. Correspondence to C.E.L. e-mail: claire.lewis@sheffield.ac.uk doi:10.1038/nrc2444 Published online 17 July 2008 T-helper-1 cell response (T H 1 response). A T H 1 immune response is mediated by pro- inflammatory cytokines such as IFNγ, IL1฀ and TNFα. It promotes cellular immune responses against intracellular infections and malignancy. T-helper-2 cell response (T H 2 response). A T H 2 response involves production of cytokines, such as IL4, that stimulate antibody production. T H 2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions. The role of myeloid cells in the promotion of tumour angiogenesis Craig Murdoch*, Munitta Muthana ‡ , Seth B. Coffelt ‡ and Claire E. Lewis ‡ Abstract | The use of various transgenic mouse models and analysis of human tumour biopsies has shown that bone marrow-derived myeloid cells, such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells, have an important role in regulating the formation and maintenance of blood vessels in tumours. In this Review the evidence for each of these cell types driving tumour angiogenesis is outlined, along with the mechanisms regulating their recruitment and activation by the tumour microenvironment. We also discuss the therapeutic implications of recent findings that specific myeloid cell populations modulate the responses of tumours to agents such as chemotherapy and some anti-angiogenic therapies. REVIEWS 618 | AUGUST 2008 | VOLUME 8 www.nature.com/reviews/cancer REVIEWS © 2008 Macmillan Publishers Limited. All rights reserved.