Abstract
BackgroundTumour stromal macrophages differentiate to tumour-associated macrophages (TAMs) with characteristics of immunosuppressive M2-type macrophages, having a central role in promoting tumour vascularisation, cancer cell dissemination and in suppressing anti-cancer immune responses. Bisphosphonates (BPs) are a group of drugs commonly used as anti-resorptive agents. Further, nitrogen containing BPs like Zoledronate (ZOL), are known to cause unspecific inflammatory reactions hence the hypothesis that its use could modulate TAMs polarization toward a more inflammatory phenotype.MethodsWe studied the in vitro polarization of J774 murine macrophages upon culture in 4T1 breast cancer cell-conditioned medium (4T1CM) and stimulation with LPS and free and liposome-encapsulated bisphosphonates.ResultsIn this system, breast cancer soluble factors reduced the pro-inflammatory activation of macrophages but increased the secretion of matrix metalloproteinases (MMPs). In the presence of 4T1CM, a non-cytotoxic dose of liposome-encapsulated ZOL (ZOL-LIP) enhanced the expression of iNOS and TNF-α, markers of M1 activation, but did not diminish the expression of M2-type markers. In contrast, clodronate treatment either as a free drug (CLO) or liposome-encapsulated (CLO-LIP) decreased the expression of the M1-type markers and was highly cytotoxic to the macrophages.ConclusionsBreast cancer cells soluble factors modulate macrophages toward M2 activation state. Bisphosphonates may be applied to counteract this modulation. We propose that ZOL-LIP may be suitable for favouring cytotoxic immune responses by TAMs in breast cancer, whereas CLO-LIP may be appropriate for TAM depletion.
Highlights
Tumour stromal macrophages differentiate to tumour-associated macrophages (TAMs) with characteristics of immunosuppressive M2-type macrophages, having a central role in promoting tumour vascularisation, cancer cell dissemination and in suppressing anti-cancer immune responses
Soluble factors from breast cancer cells influence macrophage activation The secretion of several enzymes and cytokines was affected upon macrophage culture with 3T3CM or 4T1 breast cancer cellconditioned medium (4T1CM)
The expression of the Inducible nitric oxide synthase (iNOS) enzyme was increased upon LPS stimulation of macrophages and was further upregulated upon incubation with 4T1CM followed by LPS (Figure 1A)
Summary
Tumour stromal macrophages differentiate to tumour-associated macrophages (TAMs) with characteristics of immunosuppressive M2-type macrophages, having a central role in promoting tumour vascularisation, cancer cell dissemination and in suppressing anti-cancer immune responses. The phenotype of most of the human tumour-associated macrophages (TAMs) resembles the M2 phenotype. These TAMs have been proven to support tumour growth, invasion, migration and metastasis [11]. Bisphosphonates (BPs) a class of anti-resorptive drugs are taken up by phagocytosing cells [12]. Based on their structure BPs can be divided into two categories, nonnitrogen-containing bisphosphonates (non N-BPs) and nitrogen-containing bisphosphonates (N-BPs). Both types have high affinity for bone [13]
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