Abstract
BackgroundMesenchymal stem cells (MSCs) have been reported to play an important role in tumor growth. Inflammation is an important feature of hepatocellular carcinoma (HCC). Certain inflammatory cytokines produced in tumor microenvironment modulate functional activities of MSCs. At the present time, however, the role of MSCs in the development of HCC cell resistance to chemotherapy in the inflammatory microenvironment during tumor growth has not yet been identified.MethodsMTT and PI/Annexin V-FITC assay were employed to examine the proliferation and apoptosis of HCC cell lines. The expression of TGF-β are detected by Realtime PCR and Western blot. GFP tagged LC3 expression vector and electron microscopy are utilized to demonstrate the occurrence of autophagy.ResultsWe observed that MSCs pretreated with the combination of IFN-γ and TNF-α induced resistance to chemotherapy in HCC cell lines in both the in vitro and in vivo circumstances. Following exposure to conditioned medium of MSCs that were pre-treated with IFN-γ plus TNF-α, HCC cell line cells underwent autophagy which serves as a protective mechanism for HCC cells to resist the cell toxicity of chemotherapeutic agents. Treatment of HCC cell line cells with autophagy inhibitor effectively reversed the MSCs-induced resistance to chemotherapy in these cells. Stimulation with the combination of IFN-γ and TNF-α provoked expression of TGF-β by MSCs. MSCs-induced chemoresistance in HCC cell lines was correlated with the up-regulation of TGF-β expression by MSCs. Knockdown of TGF-β expression by MSCs with siRNA attenuated MSCs-induced chemoresistance in HCC cells.ConclusionsThese results suggest that increase in TGF-β expression by MSCs in the inflammatory microenvironment of HCC promotes the development of chemoresistance in HCC cells.
Highlights
Mesenchymal stem cells (MSCs) have been reported to play an important role in tumor growth
Inflammatory cytokine-stimulated MSCs enhanced chemoresistance of hepatocellular carcinoma cells To study the effect of MSCs on the development of chemoresistance in HCC cells in inflammatory environment, we determined influence of chemotherapeutic agent cisplatin on morphological changes of HCC cell line-SMMC7721 cells in the presence of different types of conditioned media from cultures of MSCs
Conditioned medium of MSCs prestimulated with the combination of IFN-γ and TNF-α caused a significant reduction of cisplatin-induced apoptosis in cultured SMMC7721 cells
Summary
Mesenchymal stem cells (MSCs) have been reported to play an important role in tumor growth. Certain inflammatory cytokines produced in tumor microenvironment modulate functional activities of MSCs. At the present time, the role of MSCs in the development of HCC cell resistance to chemotherapy in the inflammatory microenvironment during tumor growth has not yet been identified. In addition to the chemoresistance originated from HCC cells themselves, accumulated evidences suggest that tumor microenvironment may play an important role in inducing and/or promoting the development of drug resistance. MSCs express the major histocompatibility complex (MHC) class I but do not express MHC class II, B7-1, B7-2, CD40, or CD40L molecules. They can be expanded more than 104-fold in culture without losing multilineage differentiation potential [12]. MSCs are considered as an acceptable source of stem cells in hematopoietic recovery, and an available cell type for tissue regeneration [9]
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