Figure 1

Mechanisms responsible for the accumulation of tumour-associated macrophages in hypoxic areas of solid tumours. A microenronment within a human tumour is shown containing two blood vessels and a hypoxic area (white) that has formed because it is more than 100 to 150 μm from either vessel – the critical distance for oxygenation in such tissues. Monocytes (M) pass through these vessels and are recruited into tumours by the release of the monocyte chemoattractants CCL2, 3, 4, 5 and 8 and colony-stimulating factor-1 (CSF-1) by the tumour. Once monocytes have moved across the tumour vasculature, many are attracted into hypoxic areas by the hypoxia-induced release of other monocyte attractants such as vascular endothelial growth factor (VEGF), endothelin-2 (ET-2) and endothelial-monocyte-activating polypeptide (EMAP) II. These innate cells may also be attracted into sites experiencing chronic hypoxia (and thus cell death) along a trail of necrotic debris emanating from these areas. Hypoxia then acts directly on macrophages to immobilise them and also via the upregulation of macrophage migration inhibitory factor (MIF) by tumour cells, which has a similar effect on macrophage migration (reviewed in [13]).