Model of monocyte recruitment into tumors and then TAM accumulation into hypoxic sites in tumors. (1) Elevated levels of CC chemokines and CSF-1 produced by tumors recruit monocytes from the local vasculature. (2) Once in the tumor, monocytes differentiate into TAMs. Expression of chemoattracts such as VEGF, endothelin, and EMAP II by hypoxic tumor cells can attract TAMs into hypoxic areas (brown) within tumors. (3) TAMs are retained in hypoxic/necrotic areas due to abrogation of chemotactic signal transduction, down-regulation of chemoattractant receptors, and possibly the migration inhibitory actions of MIF. (4) Once in hypoxic areas, TAMs are induced to express VEGF, which amplifies the attraction of TAMs to the area, and other factors that promote angiogenesis and tumor progression.