Host Response to Chemotherapy Induces Mesenchymal Stem Cells Activity Towards Preserving Cancer Stem Cells Niche

One of the main obstacles in clinical oncology is that tumors acquire resistance to therapy leading to their relapse and outgrowth. Numerous studies suggest that a subset of tumor cells at the tumor microenvironment, called cancer stem cells (CSCs) can substantially resist conventional therapy and was found to play a crucial role in initiating tumorigenesis and metastasis. In addition to intrinsic tumor resistance to therapy, growing body of literature shows that the host may also contribute to therapy resistance by generating pro-tumorigenic and pro-metastatic effects. In this study, we focused on mesenchymal stem cells (MSCs), since they were found to contribute to therapy resistance. MSCs home to the treated tumors and secrete a variety of factors which protect tumor cells from effects of chemotherapy. We hypothesized that MSCs may contribute to tumor resistance to therapy by preserving the CSC niche therefore allowing tumor re-growth and expansion. Our results show that MSCs massively home to PANC1 (pancreatic adenocarcinoma) tumors following Gemcitabine chemotherapy, and reside in close proximity to CSCs. MSCs exposed to Gemcitabine promote PANC1 CSC enrichment and viability in a paracrine mechanism. Furthermore, Gemcitabine-activated MSCs promote resistance to therapy and accelerate tumor growth, when co-implanted in mice with pancreatic cancer cells, in comparison to tumors co-implanted with naïve MSCs. The factors mediating the protumorigenic activity of MSCs are currently studied, with the goal to further develop drugs which can block activated MSCs thereby improving chemotherapy outcome. Overall, our study provides a possible mechanism which can explain how MSCs promote tumor resistance to therapy, and also widens our understanding of the changes occurred in the tumor microenvironment following therapy.