The roles of mesenchymal stromal cells in tumor microenvironment

Abstract

During anti-cancer treatments, large amount of apoptotic cells (AC) are released to the cancer microenvironment. Insufficient clearance of these AC may result in inflammation which can promote cancer progression. Mesenchymal stromal cells (MSCs) can be found within tumor core and constitute part of the cancer microenvironment complex. Previously, MSCs were reported to be able to engulf AC. However, little is known whether the MSCs can engulf the AC derived from cancer cells and the impact of such phagocytic process on adjacent cancer cells. Therefore, in this study, I aimed to investigate the role of MSCs in cancer microenvironment after they engulf the AC. The possible underlying mechanism will also be explored. My first step was to investigate how the AC derived from different types of cancers were taken up by MSCs and what might be the consequence of such process on tumor development. The neuroblastoma (NB) cell line SK-N-LP was used as the representative to generate the AC. My data showed that the MSCs actively engulfed the AC via phagocytosis. Furthermore, I demonstrated such engulfing process was not confined to neuroblastoma and can be applicable to various types of cancers, including leukemia, lymphoma, lung carcinoma and glioma. Interestingly, the MSCs with engulfed AC from cancers were shown to induce apoptosis of other viable cancer cells via cell-cell contact independent manner and the efficacies of such apoptotic induction varied among different types of cancers. These findings suggested that the AC treated MSCs may have anti-tumor potential. Next, I used NB as the representative to clarify the underlying mechanism of anti-tumor effect exerted by the AC treated MSCs. I also intended to find out the potential apoptosis inducers secreted from these MSCs. Both reduced cell viability and increased activation of caspase-3 in NB cells by the AC treated MSCs were observed. I then verified the apoptotic signaling pathway involved. Data shown in this study suggested that extrinsic but not intrinsic apoptotic pathway was triggered in NB cells by the AC treated MSCs. It was in part via the DR4-mediated activations of caspase-8 and caspase-3. Furthermore, IL-6 and IL-8 were shown to be increasingly secreted by MSCs after they engulfed AC. But they were not responsible for the cytotoxic effect of AC treated MSCs. Finally, I examined whether the AC treated MSCs would affect the functions of immune cells in regulating the cancer development. I demonstrated that the AC treated MSCs did not present the cytotoxic effect in normal human peripheral blood mononuclear cells (PBMCs). In particular to macrophages, it was shown that the AC treated MSCs were able to elevated their TNFα secretion. This suggested that the AC treated MSCs might exert the indirect anti-tumor effect via stimulating the anti-tumor immune responses. In conclusion, my study elucidated that after engulfing the AC by MSCs, MSCs might exert anti-tumor effect by directly inducing the apoptosis in cancer cells and indirectly promoting the secretion of TNFα in macrophages. Further detailed investigations will help to fully understand the role of AC treated MSCs in cancer evolution and the associated microenvironment.