Another route through which involution macrophages could contribute to tumor progression is by promoting angiogenesis, the formation of new capillary networks from pre-existing blood vessels. Both wound healing and tumor associated macrophages have been implicated in angiogenesis [
95]. Wound-derived macrophages have been shown in vivo to stimulate neovascularization in corneal and rabbit ear chamber angiogenesis assays [
96‐
98]. The production of several pro-angiogenic factors by wound macrophages has also been demonstrated, including IL-1, TGF-α, TGF-β, insulin-like growth factor (IGF-1), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) [
99,
100]. Wound-derived macrophages can be involved in many of the steps of angiogenesis including induction of endothelial cell chemotaxis, proliferation and matrix synthesis [
101]. TAM share many of the pro-angiogenic abilities of wound-derived macrophages. The pro-angiogenic cytokines VEGF, TGF-α, and PDGF are also released by TAM when in hypoxic environments, as well as IL-8, basic FGF (bFGF), and prostaglandin E
2 (PGE
2) [
102]. Several mouse models have demonstrated a distinct role for macrophages in the ‘angiogenic switch’ required for malignant progression. In a human xenograft model of breast cancer, the depletion of CSF-1 by anti-sense oligonucleotides, siRNAs or antibodies resulted in reduced angiogenesis as well as decreased tumor progression [
32,
33]. Direct evidence for macrophage-induced tumor angiogenesis comes from a model where Tie2-expressing macrophages are recruited to tumors [
103]. Ablation of these macrophages reduces both tumor angiogenesis and tumor growth [
103]. Consistent with this study, F4/80 positive macrophage infiltration occurs just before increased tumor vessel density in the MMTV-PyMT model [
104]. When the macrophages were depleted by genetic cross into the CSF-1 null background, the angiogenic switch was significantly delayed, and a 50% decrease in vascular density occurred [
104]. In another study, tet-inducible MMTV-VEGF-A mice were crossed with the PyMT/CSF-1 null mice to determine whether the loss of macrophage angiogenic function could be restored by VEGF-A alone. The angiogenic switch was restored as well as tumor progression [
105]. As the primary cellular source for pro-angiogenic VEGF-A in the PyMT model is TAM, this study highlights the promotional role macrophages have in tumor angiogenesis [
104]. Clinical breast cancer data also support a relationship between macrophages and angiogenesis, as increased TAM number correlates with high vascular grades of breast tumors and with poor prognosis in multiple studies [
4,
14,
99].
Under non-cancer conditions, involution macrophages are not likely to be pro-angiogenic, but could be promoted to this state by the presence of tumor cells. While angiogenesis is highly upregulated during the pregnant and lactational periods of mammary gland development, during involution the intricate capillary networks required for lactation regress through currently unknown mechanisms [
106]. While it is difficult to detect apoptotic endothelial cells during involution, the vessel organization returns to the simple, pre-pregnant network within 10 days post-weaning [
107]. Concurrently, there is a progressive decrease in VEGF and VEGF-receptor RNA levels [
108]. However, based on the known plastic response of macrophages to various environmental cues, we propose that involution macrophages are poised to respond to the presence of cancer cells by switching to an angiogenic phenotype.