Abstract

BackgroundMacrophages are highly versatile cells that play an important role in tumour microenvironment. Tumour associated macrophages (TAMs) have been linked to both, good or bad prognosis of several cancer types depending on their number, composition and polarization. Viscum album lipophilic extract (VALE) contains several pentacyclic triterpenes known to modulate the activity of monocytes and other immune cells and to exhibit anticancer properties. In our in vitro study, we investigated the effect of tumour cell lines on macrophage polarization and monocyte chemotactic transmigration and examined the modulatory potential of VALE and its predominant triterpene oleanolic acid (OA).MethodsHuman peripheral blood monocytes were differentiated into monocyte derived macrophages (MDM) using M-CSF and polarized into M1 by IFN-γ and LPS and into M2 macrophages by IL-4 and IL-13 or by co-culture with two different tumour cell lines. Polarized macrophages were subsequently treated with VALE or OA. Phenotypic markers and cytokines were assessed by flow cytometry and immunoanalysis. Migration of human peripheral blood monocytes induced by monocyte chemotactic protein-1 (MCP-1) or supernatants of different tumour cell lines under the influence of VALE or OA was measured in a chemotaxis transmigration assay.ResultsIn vitro polarized M1 and M2 type macrophages revealed specific phenotypic patterns and tumour cell co-cultured MDM displayed ambiguous phenotypes with M1 as well as M2 associated markers. VALE and OA showed modest influence on cell surface marker profile and cytokine expression of tumour cell co-cultured macrophages. All tumour cell supernatants markedly enhanced the migratory activity of monocytes. VALE and OA significantly inhibited MCP-1 induced monocyte transmigration, whereas monocyte migration initiated by tumour cell derived supernatants was not affected.ConclusionsIn our study we reconfirmed that co-culture with different tumour cell lines can result in a mixed macrophage phenotype with M1 as well as M2 patterns, a finding that is important for a better understanding of tumour microenvironment functions. Moreover, we demonstrated that VALE shows slight immunomodulatory effects on tumour cell co-cultured macrophages and modulates monocyte chemotactic transmigration in vitro, indicating promising possibilities of triterpenes from Viscum album L. to contribute in a multimodal concept of anti-cancer therapy in future. Our data contribute to an understanding of monocyte function and macrophage polarization in vitro and of the possibility to influence their behaviour by triterpene containing mistletoe extracts.

Highlights

  • Macrophages are highly versatile cells that play an important role in tumour microenvironment

  • Polarization of macrophages with tumour cell lines led to a mixed M1/M2 phenotype Freshly isolated monocytes were differentiated into monocyte derived macrophages (MDM) with M-CSF before polarization into M1 using IFN-γ and LPS or into M2 macrophages by IL-4 and IL-13, or were co-cultured with NCI-H460 or MCF-7 tumour cells to better mimic a realistic situation of macrophage polarization by tumours

  • M1 macrophages significantly enhanced the relative expression of CD40 (p < 0.001) and IL-6 (p = 0.019) and M2 macrophages enhanced the relative expression of CD11b (p < 0.001), CD36 (p = 0.008), CD206 (p < 0.002) and HLADR (p = 0.028) compared to the opposite polarization phenotype

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Summary

Introduction

Macrophages are highly versatile cells that play an important role in tumour microenvironment. Tumour associated macrophages (TAMs) have been linked to both, good or bad prognosis of several cancer types depending on their number, composition and polarization. In our in vitro study, we investigated the effect of tumour cell lines on macrophage polarization and monocyte chemotactic transmigration and examined the modulatory potential of VALE and its predominant triterpene oleanolic acid (OA). The microenvironment of tumours is a subject of great interest in current investigations on cancer treatment and is known to play a crucial role in terms of neoangiogenesis, inflammation and modulation of the immune system [1,2,3]. It has been shown that macrophages play an important role in the microenvironment of tumours [4]. Investigation on how to modulate these cells alone or in presence of tumour cells is an important aspect in current research

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