Abstract
BackgroundTumour-derived microvesicles (TMVs) are important players in tumour progression, modulating biological activity of immune cells e.g. lymphocytes, monocytes and macrophages. This phenomenon is particularly interesting in the progression of colon cancer, as macrophages in this type of tumour are relevant for the recovery processes. In the present study, the role of colon cancer cell-derived microvesicles in monocyte differentiation and activity profile (polarization) was investigated.MethodsMonocyte-derived macrophages (MDM) were differentiated in vitro in the presence of TMVs obtained from colon cancer: Caco-2, SW620, LoVo or SW480 cell lines and analysed according to their morphology and biological functions, as defined by cytokine secretion, reactive oxygen intermediate (ROI) production and cytotoxic activity against respective colon cancer cells.ResultsMonocytes differentiated with TMVs exhibited morphological and phenotypical characteristics of macrophages. An early contact (beginning with the first day of the in vitro culture) of monocytes with TMVs resulted in increased IL-10 secretion and only slightly elevated TNF release. Early, or prolonged contact resulted in low ROI production and low cytotoxicity against tumour cells. On the other hand, late contact of MDM with TMVs, stimulated MDM to significant TNF and IL-12 secretion, ROI production and enhanced cytotoxicity against tumour cells in vitro. In addition, differences in MDM response to TMVs from different cell lines were observed (according to cytokine secretion, ROI production and cytotoxicity against tumour cells in vitro). Biological activity, STATs phosphorylation and microRNA profiling of MDMs indicated differences in their polarization/activation status which may suggest mixed polarization type M1/M2 with the predominance of proinflammatory cells after late contact with TMVs.ConclusionsMacrophage activity (polarization status) may be regulated by contact with not only tumour cells but also with TMVs. Their final polarization status depends on the contact time, and probably on the vesicle “cargo”, as signified by the distinct impact of TMVs which enabled the switching of MDM maturation to regulatory macrophages.
Highlights
Tumour-derived microvesicles (TMVs) are important players in tumour progression, modulating biological activity of immune cells e.g. lymphocytes, monocytes and macrophages
Our results indicate an important role of TMVs in this process and suggest that TMVs origin and the time of their “first contact” with monocytes/ macrophages are crucial for their ultimate activity and function
Spindlelike Monocyte-derived macrophages (MDM), which resembled cells cultured with macrophage colony-stimulating factor (M-CSF) (Fig. 2h) were more frequent when TMVs were added at 0d
Summary
Tumour-derived microvesicles (TMVs) are important players in tumour progression, modulating biological activity of immune cells e.g. lymphocytes, monocytes and macrophages. EVs are released by tumour cells, impacting the activity of blood monocytes and TAM in tumour bed [17] Based on their cargo (proteins, growth factors, mRNA and microRNAs) EV are regarded as “messengers” [12,13,14,15], which may affect biological activity of macrophages. We asked whether TMVs released by colon cancer cell lines (with different growth potential) may influence monocyte differentiation, affecting their activity/polarization status. In another words, we asked, if TMVs, as tumour “go-between” present in body fluids/ tumour environment, may direct/educate monocytes during their differentiation. Our results indicate an important role of TMVs in this process and suggest that TMVs origin and the time of their “first contact” with monocytes/ macrophages are crucial for their ultimate activity and function
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