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.

Macrophages Are More Potent Immune Suppressors Ex Vivo Than Immature Myeloid-Derived Suppressor Cells Induced by Metastatic Murine Mammary Carcinomas

“…In addition, agents that target multiple populations of myeloid cells may be especially effective in combination with immunotherapy. Treatments such as clodronate have been used previously to target phagocytic myeloid cells, including both MDSCs and Mfs (47,48), and have been shown to reduce tumor growth and metastasis (49). Similarly, depletion of myeloid cells via Abs common to multiple myeloid cell subsets (i.e., CD11b, Gr1, or F4/80) may also aid in reducing tumor growth and/or metastasis (50).…”

Anti‐tumor activity of CpG‐ODN aerosol in mouse lung metastases

“…delivery of CpG-ODN in the B16 melanoma model stimulated a strong expansion of NK cells and induced significant protection against lung metastases, while CpG aerosol treatment failed to modify the number of NK cells in lung and did not confer significant protection. Depletion of lung macrophages by liposome encapsulated clodronate, a bisphosphonate compound, 47 allowed aerosolized CpG-ODN to expand NK cells and reduce the number of lung metastases. Aerosol inhalation to deliver Cl 2 MDPliposomes to the lung has been recently reported, 48 raising the possibility of aerosolized bisphosphonates in clinical use.…”

Effects of Bisphosphonate on the Expression of Matrix Enzymes during Endochondral Ossification

“…MMP-9 (gelatinase B) has been identified in the articular tissues and shown to be increased in OA cartilage along with MMP-2 (gelatinase A). MMP-9 is expressed in osteoclasts during the development of the marrow cavity in long bones, releasing VEGF from the matrix [25]. In the present study, in vitro treatment of alendronate on chondrocytes with various concentrations from 10 -3 M to 10 -6 M reduced MMP-9 expression in a dose-dependent manner.…”