RT Journal Article
SR Electronic
T1 Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 482513
DO 10.1101/482513
A1 Augustin Le Naour
A1 Mélissa Prat
A1 Benoît Thibault
A1 Renaud Mével
A1 Léa Lemaitre
A1 Hélène Leray
A1 Muriel Golzio
A1 Lise Lefevre
A1 Eliane Mery
A1 Alejandra Martinez
A1 Gwénaël Ferron
A1 Jean-Pierre Delord
A1 Agnès Coste
A1 Bettina Couderc
YR 2018
UL http://biorxiv.org/content/early/2018/12/04/482513.abstract
AB Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. We determine the mechanisms by which a naïve MSC could become a CA-MSC and characterize CA-MSCs. Ovarian tumor cells (OTC) trigger the transformation of MSCs to CA-MSCs expressing different pro-tumoral, genes and secreting high amounts of CXCR1/2 ligands (CXCL1, CXCL2 and IL-8) implicated in the chemoresistance of cancer cells. CXCR1/2 ligands can also inhibit the immune response against OTC. Indeed, through their released factors, CA-MSCs can trigger the differentiation of monocytes to pro-tumoral M2 phenotype macrophages known to promote the tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 functions and acquire an anti-tumoral phenotype. Both ex vivo and in vivo a CXCR1/2 inhibitor can sensitize OTC to carboplatin even in the presence of a pro-tumoral microenvironment. This inhibitor can circumvent the pro-tumoral effects of CA-MSCs. As high concentrations of CXCR1/2 ligands in blood from patients can be associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert chemoresistance.