Tumour macrophages as potential targets of bisphosphonates

Abstract

Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use.Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to bisphosphonates in model studies; In vitro, zoledronic acid causes increased apoptotic cell death; in vivo the drug has been shown to inhibit the production of pro-angiogenic factor MMP-9, as well as most recent evidence showing it can trigger the reversal of the TAMs phenotype from pro-tumoral M2 to tumoricidal M1. There is thus accumulating evidence supporting the hypothesis that effects on TAMs may contribute to the anti-tumour effect of bisphosphonates. This review will focus in detail on the role of tumour associated macrophages in breast cancer progression, the actions of bisphosphonates on macrophages in vitro and in tumour models in vivo and summarise the evidence supporting the potential for the targeting of tumour macrophages with bisphosphonates.

Figure 1

Development of different types of macrophages from multipotent hematopoetic stem cells.

Figure 2

Role of tumour associated macrophages in tumour progression.

Figure 3

Structure of pyrophosphonate (top left), general structure of a bisphosphonate (top right), structure of clodronate (bottom left), alendronate (bottom middle) and zoledronic acid (bottom right).

Figure 4

Schematic diagram of the mevalonate pathway for cholesterol synthesis. Nitrogen-containing bisphosphonates (N-BPs) inhibit farnesyl diphosphate (FPP) synthase, preventing synthesis of farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) required for the prenylation of a number of key proteins essential for cell survival. Inhibition of FPP synthase also causes the accumulation of isopentenyl diphosphate (IPP), which is incorporated into the cytotoxic metabolite ApppI (triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester). Statins also act through this pathway by inhibition of HMG-CoA reductase.

Figure 5

The Vicious Cycle of Cancer-induced bone disease.