Figure 8. Zoledronate targets the pro-tumourigenic macrophage microenvironment.

Monocytes can be polarized into two distinct types of macrophages, M1 and M2, using phorbol 12-myristate 13-acetate (PMA), interferon gamma (IFN-γ) and lipopolysaccharide (LPS) or PMA and interleukin 4 (IL-4) and interleukin 13 (IL-13) respectively. M1 macrophages, classically referred to as “pro-inflammatory macrophages” are known to secrete many factors such as tumour necrosis factor alpha (TNF-α) and reactive oxygen species (ROS) and likely unknown factors. Within our model M1 macrophages stimulate breast cancer migration. M2 macrophages classically referred to as “pro-tumourigenic macrophages” are known to secrete numerous factors including matrix metalloproteinase's (MMPs) and epidermal growth factor (EGF). Within our model M2 macrophages stimulate breast cancer migration and stem cell-like activity. The interaction between macrophages and cancer cells is bi-directional whereby cancer cells also secrete proteins, for example colony stimulating factor (CSF) which recruits M2 macrophages to the tumour. Zoledronate inhibits the effects that both M1 and M2 macrophages exert upon breast cancer cells, with no direct effect on the breast cancer cells in the absence of a macrophage microenvironment. The mechanism of action of Zoledronate is therefore likely to effect the interaction between macrophages and breast cancer cells.