Abstract
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.
Highlights
Chemoresistance is a major problem in the treatment of cancer
To evaluate the ability of cancer-associated mesenchymal stromal cells (CA-mesenchymal stromal cells (MSCs)) to induce chemoresistance in ovarian tumor cells (OTCs), we cultured the human OTC line IGROV-1 in conditioned media (CM) from CA-MSCs, and treated them with carboplatin, the standard-of-care in ovarian cancer treatment
Since CA-MSC and induced CA-MSC (iCA-MSC) induced a modification of the macrophage tumoricidal activity, and because this observation could be associated with a difference in CXCL1/2 and interleukin 8 (IL-8) secretions between these cells, we evaluated the impact of CXC chemokine receptors 1 and 2 (CXCR1/2) inhibition on the ability of macrophages cultured in CA-MSC CM to kill OTCs
Summary
Chemoresistance is a major problem in the treatment of cancer. In the case of ovarian tumors, resistance can occur during treatment, or several months later, and is generally associated with a dismal prognosis. The acquired chemoresistance within the tumor cells can be caused by molecular alterations affecting metabolism, growth control and apoptosis pathways, uptake, or efflux of the drug (Lønning et al, 2013).
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