Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas

Angiogenesis is essential to the growth and metastasis of solid tumours. Va scular endothelial growth factor (VEGF) as a potent pro-angiogenic cytokine that is overexpresses in malignant tumours such as invasive carcinoma of t he breast. The low oxygen tensions (hypoxia) present in these tumours are k nown to up-regulate the expression of VEGF by tumour cells. Human macrophag es also respond to hypoxia by increasing their release of VEGF in vitro, al though the effect of hypoxia on VEGP expression by macrophages irt vivo has yet to be demonstrated. The present study compared the expression of VEGP by macrophages in areas of low and high vascularity in 24 invasive breast c arcinomas (12 lobular, 12 ductal), The cellular distributions of VEGF prote in, CD31 (vessels), and CD68 (macrophages),were compared in sequential sect ions for each tumour. In ten tumours, both tumour cells and macrophages wer e immunoreactive for VEGF protein. Use of non-isotopic in situ hybridizatio n to localize VEGF mRNA showed that these cell types also expressed VEGF mR NA. No significant differences in the cellular distribution of VEGF protein mere found between lobular and ductal carcinomas. In all tumours, macropha ges accumulated in higher numbers in poorly vascularized than in highly vas cularized areas. In VEGF-positive tumours, macrophages were immunoreactive for VEGF only in avascular areas where tumour cells also expressed VEGF, Th is suggests that VEGF expression by these two cell types may be regulated b y the same microenvironmental stimuli in breast carcinomas. In addition, si gnificantly more macrophages mere present in poorly vascularized areas of V EGF-positive than VEGF-negative tumours. This suggests that VEGF may exert a chemotactic action on macrophages in vivo and guide their migration into avascular tumour sites. Copyright (C) 2000 John Wiley & Sons, Ltd.