Mesenchymal stromal cells (MSCs) are inherently tumour-homing and can be isolated, expanded and transduced, making them viable candidates for cell therapy. This tumour-tropism has been used to deliver anti-cancer therapies to various tumour models in several organs. In a previous study we have shown that MIF is the key director of MSC migration and infiltration towards tumour cells. We have shown this major role for MIF (mainly via CXCR4), using in vitro migration and invasion assays, in presence of different receptor inhibitors and achieving a drastic decrease in both processes using MIF inhibitor. Importantly we show that knock down of either CXCR4 or MIF abrogates MSC homing to tumours in an in vivo pulmonary metastasis model, confirming the in vitro 2D and 3D assays. In this study we define the mechanism behind MIF stimulation of MSC homing to tumours. We show that MIF upregulates other cytokines involved in chemotaxis, such as IL6, IL8 and CCL2 and upregulates MIF as well, amplifying the initial trigger and generating a positive feedback loop. However when inhibiting those cytokines individually, we never achieved a decrease in migration as drastic as for MIF inhibition. This suggests that the up-regulation of this set of cytokines would lead to chemoattraction of leucocytes to the site of the tumour, which was observed in a 3D model. Therefore, MIF trigger is amplified by its own upregulation in MSCs via a positive feedback loop, confirming again our previous findings and its key role as a regulator of MSC homing to tumours. This improved understanding of MSC tumour tropism will further enable development of novel cellular therapies for cancers.
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