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Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma.

ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is a type of cancer that is difficult to cure; chemoresistance of cholangiocarcinoma cells affect the prognosis of patients who cannot be treated with surgery. The mechanism underlying this chemoresistance remains unknown. Mesenchymal stem cells (MSCs) are known to be important components of the tumor microenvironment. In the present study, a large number of MSCs were observed to infiltrate the tumor sites of ICC; thus, MSCs were isolated from ICC tumor tissues. It was revealed that herpesvirus entry mediator (HVEM) was overexpressed in ICC?MSCs. The present study then investigated the role of HVEM?overexpressing MSCs in the chemoresistance of cholangiocarcinoma cells. It was demonstrated that HVEM?overexpressing MSCs could support cell survival of chemotherapeutic cholangiocarcinoma cells and inhibited their apoptosis. Further investigations revealed that HVEM?overexpressing MSCs could secrete IL?6 and also activated AMPK/mTOR?dependent autophagy of cholangiocarcinoma cells. Thus, it was concluded that ICC?MSC?induced autophagy is the primary cause of chemoresistance in ICC.

SUBMITTER: Gan L

PROVIDER: S-EPMC7709831 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma.

Gan Linhe L Shen Hao H Li Xinduo X Han Zhipeng Z Jing Yingying Y Yang Xue X Wu Mengchao M Xia Yong Y

Oncology reports 20201106 1

Intrahepatic cholangiocarcinoma (ICC) is a type of cancer that is difficult to cure; chemoresistance of cholangiocarcinoma cells affect the prognosis of patients who cannot be treated with surgery. The mechanism underlying this chemoresistance remains unknown. Mesenchymal stem cells (MSCs) are known to be important components of the tumor microenvironment. In the present study, a large number of MSCs were observed to infiltrate the tumor sites of ICC; thus, MSCs were isolated from ICC tumor tiss ...[more]

PMID: 33155663

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Project description:BackgroundThe tumour microenvironment contributes to chemotherapy resistance in gliomas, and glioma-associated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. However, whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. Herein, we explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells.MethodsHuman glioma cells (cell line U87MG and primary glioblastoma cell line GBM-1) were cultured in conditioned media of gaMSCs and further treated with TMZ. The proliferation, apoptosis and migration of glioma cells were detected by Cell Counting Kit-8 (CCK-8), flow cytometry and wound-healing assays. The expression of FOXS1 in glioma cells was analysed by gene microarray, PCR and Western blotting. Then, FOXS1 expression in glioma cells was up- and downregulated by lentivirus transfection, and markers of the epithelial-mesenchymal transformation (EMT) process were detected. Tumour-bearing nude mice were established with different glioma cells and treated with TMZ to measure tumour size, survival time and Ki-67 expression. Finally, the expression of IL-6 in gaMSC subpopulations and its effects on FOXS1 expression in glioma cells were also investigated.ResultsConditioned media of gaMSCs promoted the proliferation, migration and chemotherapy resistance of glioma cells. The increased expression of FOXS1 and activation of the EMT process in glioma cells under gaMSC-conditioned media were detected. The relationship of FOXS1, EMT and chemotherapy resistance in glioma cells was demonstrated through the regulation of FOXS1 expression in vitro and in vivo. Moreover, FOXS1 expression in glioma cells was increased by secretion of IL-6 mainly from the CD90low gaMSC subpopulation.ConclusionsCD90low gaMSCs could increase FOXS1 expression in glioma cells by IL-6 secretion, thereby activating epithelial-mesenchymal transition and resistance to TMZ in glioma cells. These results indicate a new role of gaMSCs in chemotherapy resistance and provide novel therapeutic targets.

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Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma.

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Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma.

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