Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve 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) ligand 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.

中文翻译：

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肿瘤细胞教育间充质基质细胞释放化学保护和免疫调节因子。

周围细胞释放的因子，例如癌症相关的间充质基质细胞（CA-MSC），参与了肿瘤的进展和化学抗药性。在这项研究中，我们表征了幼稚的间充质基质细胞（MSCs）可以获取CA-MSCs表型的机制。卵巢肿瘤细胞通过表达与癌细胞化学抗性有关的促肿瘤基因，触发MSC向CA-MSC的转化，导致分泌高水平的CXC趋化因子受体1和2（CXCR1 / 2）配体，例如趋化因子（ CXC基序）配体1（CXCL1），CXCL2和白介素8（IL-8）。CXCR1 / 2配体还可以抑制针对卵巢肿瘤细胞的免疫反应。实际上，通过其释放的因子，CA-MSC促进了单核细胞向M2巨噬细胞的分化，这有利于肿瘤的进展。当CXCR1 / 2受体被抑制时，这些CA-MSC活化的巨噬细胞失去其M2特性并获得抗肿瘤表型。在离体和体内，我们都使用CXCR1 / 2抑制剂使卵巢肿瘤细胞对卡铂敏感，并规避了CA-MSC的促肿瘤作用。由于患者血液中高浓度的CXCR1 / 2配体与化学耐药性相关，因此抑制CXCR1 / 2可能是恢复卡铂耐药性的潜在治疗策略。