The vitamin K-dependent factor, protein S, regulates brain neural stem cell migration and phagocytic activities towards glioma cells.

Affiliation

Laboratoire Signalisations et Transports Ioniques Membranaires (STIM), CNRS ERL 7003 Equipe 4CS - Université de Poitiers, UFR SFA, Pôle Biologie Santé, Bâtiment B36, 1 Rue Georges Bonnet, TSA 51106, 86073, POITIERS Cedex 9, France; Micronit GDR CNRS 3697, 75020, Paris, France. Electronic address: [Email]

Abstract

Malignant gliomas are the most common primary brain tumors. Due to both their invasive nature and resistance to multimodal treatments, these tumors have a very high percentage of recurrence leading in most cases to a rapid fatal outcome. Recent data demonstrated that neural stem/progenitor cells possess an inherent ability to migrate towards glioma cells, track them in the brain and reduce their growth. However, mechanisms involved in these processes have not been explored in-depth. In the present report, we investigated interactions between glioma cells and neural stem/progenitor cells derived from the subventricular zone, the major brain stem cell niche. Our data show that neural stem/progenitor cells are attracted by cultured glioma-derived factors. Using multiple approaches, we demonstrate for the first time that the vitamin K-dependent factor protein S produced by glioma cells is involved in tumor tropism through a mechanism involving the tyrosine kinase receptor Tyro3 that, in turn, is expressed by neural stem/progenitor cells. Neural stem/progenitor cells decrease the growth of both glioma cell cultures and clonogenic population. Cultured neural stem/progenitor cells also engulf, by phagocytosis, apoptotic glioma cell-derived fragments and this mechanism depends on the exposure of phosphatidylserine eat-me signal and is stimulated by protein S. The disclosure of a role of protein S/Tyro3 axis in neural stem/progenitor cell tumor-tropism and the demonstration of a phagocytic activity of neural stem/progenitor cells towards dead glioma cells that is regulated by protein S open up new perspectives for both stem cell biology and brain physiopathology.

Keywords

Brain subventricular zone,Cancer,Glioma,Neural stem cell,TAM tyrosine kinase receptors,Vitamin K-Dependent protein,

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