Chemoresistance Acquisition by Ovarian Adenocarcinoma Cells due to the Crosstalks between MSCs and Macrophages

It is well established that the tumor microenvironment plays a role in modulating the sensitivity of tumor cells to cytotoxic agents. We have shown that cancer associated –mesenchymal stromal cells (CA-MSC) are involved not only on the tumor progression but also in the acquisition of drugs resistance of ovarian adenocarcinoma cells via, among others, secreted molecules in vitro and in vivo. Our aim is to identify the mechanisms by which CA-MSC activate tumor cells signaling pathway for both effects. First we showed that factors released by CA-MSC are able to induce angiogenic cytokines (IL-6, IL-8 and VEGF) synthesis by tumor cells in a cell line specific way. Second, CA-MSC are able to attract and activate macrophages into a M2 TAM like phenotype and allow them to secrete a huge quantity of pro-angiogenic cytokines, favorable to tumor progression of all the associated ovarian adenocarcinoma cells tested. Third, factors released by CA-MSC protect adenocarcinoma cells from carboplatin-induced apoptosis by inhibiting the activation of effector caspases 3 and 7, inducing the activation of PI3K/Akt pathway signalling and the phosphorylation of the downstream target XIAP (caspase inhibitor from IAP family). XIAP depletion by siRNA strategy or inhibitors permitted to restore carboplatin-induced apoptosis in ovarian cancer cells stimulated by CA-MSC conditioned medium.

This work has already served as the basis for the establishment of a clinical trial using inhibitors of cIAP. Our results suggested targeting factors released by CA-MSC such as IL-6 or IL-8 in combination with conventional therapies could be of interest in ovarian cancer therapy.