Tumor hypoxia modulates podoplanin/CCL21 interactions in CCR7+ NK cell recruitment and CCR7+ tumor cell mobilization
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Anna Tejchman1,2, Nathalie Lamerant-Fayel1, Jean-Claude Jacquinet3, Aleksandra Bielawska-Pohl2, Katarzyna Mleczko-Sanecka1, Catherine Grillon1, Salem Chouaib4, Maciej Ugorski2 and Claudine Kieda1,5
1Centre for Molecular Biophysics, UPR 4301 CNRS affiliated to Orléans University and INSERM, Orléans, France
2Laboratory of Glycobiology and Intercellular Interactions, Institute of Immunology and Experimental Therapy, PAN, Wroclaw, Poland
3ICOA, UMR CNRS 7311, University of Orleans, Orleans, France
4INSERM U1186, Gustave Roussy Institute, Villejuif, France
5Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
Claudine Kieda, email: [email protected]
Keywords: adhesion, cancer associated fibroblasts, CCL21, hypoxia, podoplanin
Received: June 29, 2016 Accepted: October 21, 2016 Published: March 17, 2017
Podoplanin (PDPN), an O-glycosylated, transmembrane, mucin-type glycoprotein, is expressed by cancer associated fibroblasts (CAFs). In malignant transformation, PDPN is subjected to changes and its role is yet to be established. Here we show that it is involved in modulating the activity of the CCL21/CCR7 chemokine/receptor axis in a hypoxia-dependent manner. In the present model, breast cancer MDA-MB-231 cells and NKL3 cells express the surface CCR7 receptor for CCL21 chemokine which is a potent chemoattractant able to bind to PDPN. The impact of the CCL21/CCR7 axis in the molecular mechanism of the adhesion of NKL3 cells and of MDA-MB-231 breast cancer cells was reduced in a hypoxic tumor environment. In addition to its known effect on migration, CCL21/CCR7 interaction was shown to allow NK cell adhesion to endothelial cells (ECs) and its reduction by hypoxia. A PDPN expressing model of CAFs made it possible to demonstrate the same CCL21/CCR7 axis involvement in the tumor cells to CAFs recognition mechanism through PDPN binding of CCL21. PDPN was induced by hypoxia and its overexpression undergoes a reduction of adhesion, making it an anti-adhesion molecule in the absence of CCL21, in the tumor. CCL21/CCR7 modulated NK cells/ECs and MDA-MB-231 cells/CAF PDPN-dependent interactions were further shown to be linked to hypoxia-dependent microRNAs as miRs: miR-210 and specifically miR-21, miR-29b which influence PDPN expression.
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