Tumor-associated macrophages (TAMs) produce angiogenic factors and in
breast cancer are associated with high vascular grade and poor survival. TAMs preferentially migrate to hypoxic areas within
tumors and strongly express
hypoxia-inducible factor (HIF)-2 alpha. This study examined whether
HIF-2 alpha was involved in TAM angiogenic activation by correlating its expression with
tumor microvessel density as a marker of angiogenesis, and other
tumor variables, in a series of human primary invasive
breast carcinomas. A correlation was found between high TAM
HIF-2 alpha and high
tumor vascularity (P < 0.0001), as well as high
tumor grade (P = 0.007). The relation of
HIF-2 alpha expression to a recently described
oxygen-dependent pathway of angiogenesis was also studied, and an inverse relationship was found between TAM
HIF-2 alpha and
tumor thymidine phosphorylase expression (P = 0.02). These results suggest that TAM HIF-2 signaling may be a useful target for future antiangiogenic strategies but show that
tumors use both
oxygen-dependent and
oxygen deficiency-regulated pathways for angiogenesis. Thus, combined blockade of pathways and careful assessment of these pathways in trials are necessary.