MicroRNAs as the critical regulators of Cisplatin resistance in ovarian cancer cells

Background Ovarian cancer (OC) is one of the leading causes of cancer related deaths among women. Due to the asymptomatic tumor progression and lack of efficient screening methods, majority of OC patients are diagnosed in advanced tumor stages. A combination of surgical resection and platinum based-therapy is the common treatment option for advanced OC patients. However, tumor relapse is observed in about 70% of cases due to the treatment failure. Cisplatin is widely used as an efficient first-line treatment option for OC; however cisplatin resistance is observed in a noticeable ratio of cases. Regarding, the severe cisplatin side effects, it is required to clarify the molecular biology of cisplatin resistance to improve the clinical outcomes of OC patients. Cisplatin resistance in OC is associated with abnormal drug transportation, increased detoxification, abnormal apoptosis, and abnormal DNA repair ability. MicroRNAs (miRNAs) are critical factors involved in cell proliferation, apoptosis, and chemo resistance. MiRNAs as non-invasive and more stable factors compared with mRNAs, can be introduced as efficient markers of cisplatin response in OC patients. Main body In present review, we have summarized all of the miRNAs that have been associated with cisplatin resistance in OC. We also categorized the miRNAs based on their targets to clarify their probable molecular mechanisms during cisplatin resistance in ovarian tumor cells. Conclusions It was observed that miRNAs mainly exert their role in cisplatin response through regulation of apoptosis, signaling pathways, and transcription factors in OC cells. This review highlighted the miRNAs as important regulators of cisplatin response in ovarian tumor cells. Moreover, present review paves the way of suggesting a non-invasive panel of prediction markers for cisplatin response among OC patients.

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

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.

Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization

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.