Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors

• 来源期刊: 分子细胞生物学报（英文版）
• 年，卷（期）: 2020,（3）
• 页码范围: 202-215
• 页数: 14页
• 语种: 英文
• DOI: 10.1093/jmcb/mjz090

摘要

Factors released by surrounding cells such as cancer-associated mesenchymai stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance.In this study,we characterize the mechanisms by which na(i)ve mesenchymal stromal cells (MSCs)can acquire a CA-MSCs phenotype.Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells,resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) iigand 1 (CXCL1),CXCL2,and interleukin 8 (IL-8).CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells.Indeed,through their released factors,CA-MSCs promote the differentiation of monocytes towards M2 macrophages,which favors tumor progression.When CXCR1/2 receptors are inhibited,these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype.Both ex vivo and in vivo,we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs.Since high concentrations of CXCR1/2 ligands in patients' blood are associated with chemoresistance,CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.