The development of a tumor vasculature, termed the angiogenic switch, is a crucial step for the survival and metastasis of malignant tumors. However, the biological regulation of the process is largely unknown. Using genetic approaches to alter the infiltration and function of macrophages in a transgene-induced mouse model of mammary tumorigenesis, the authors show that tumor-associated macrophages play an important role in promoting this process (top panels). The authors find that the onset of the angiogenic switch, identified as the formation of a high-density vessel network, is restricted to the sites of malignant transformation in the heterogeneous tumor (top left). This angiogenic switch occurs subsequent to an increase in macrophage infiltration (bottom panels). Inhibition of this infiltration delays the angiogenic switch and the transition to malignancy (top right), while restoration of the macrophage population rescues these phenotypes. Furthermore, premature induction of macrophage infiltration into premalignant lesions promotes an early onset of the angiogenic switch independent of tumor progression. These findings indicate that macrophages play a key regulatory role in tumor angiogenesis. Identification of the mechanism(s) macrophages employ to promote the angiogenic switch therefore will be very important for the development of novel and effective therapeutic strategies against tumors. For details, see the article by Lin et al. on page 11238 of this issue.

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