Niche origin of mesenchymal stem cells derived microvesicles determines opposing effects on NSCLC: Primary versus metastatic |
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| Institution: | 1. Lung Cancer Research, Lung Cancer Unit, Meir Medical Center, Kfar Saba 44281, Israel;2. Oncogenetic Laboratories, Meir Medical Center, Kfar Saba 44281, Israel;3. Oncology Department, Meir Medical Center, Kfar Saba 44281, Israel;4. Sackler Faculty of Medicine, Tel Aviv University Ramat Aviv, Tel Aviv 69978, Israel;1. The State Key Lab of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiangxi Road, Guangzhou, 510120, China;2. The School of Public Health, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou, 510182, China;3. Department of Genetics, Medical College of Soochow University, 1 Shizi Road, Suzhou, 215123, China;4. The Third Affiliated Hospital of Guangzhou Medical University, 63 duobao Road, Guangzhou, 510120, China;1. Division of Thoracic Surgery, Swedish Cancer Institute, Seattle, Washington;2. Seattle Radiologists, Seattle, Washington;3. CellNetix Pathology and Laboratories, Seattle, Washington;1. Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Múnich, Alemania;2. Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Alemania;3. Departamento de Cardiología, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria INCLIVA, Universidad de Valencia, Valencia, España;4. Klinik für Herz-, Thorax-, und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg, Alemania;5. Universitäres Herzzentrum, Kardiologie, Universitätsspital Zürich, Zúrich, Suiza;6. Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site Munich Heart Alliance, Múnich, Alemania;1. Department of Genetics, Cancer Research Institute of SAS, Bratislava, Slovak Republic;2. Faculty of Medicine, Second Department of Oncology, Comenius University, National Cancer Institute, Bratislava, Slovak Republic;3. Faculty of Medicine, Institute of Pathological Anatomy, Comenius University, University Hospital, Bratislava, Slovak Republic;4. Department of Surgical Oncology, National Cancer Institute, Bratislava, Slovak Republic;5. Department of Plastic, Aesthetic and Reconstructive Surgery, University Hospital, Bratislava, Slovak Republic;6. Faculty of Medicine, Institute of Medical Biology, Genetics and Clinical Genetics, Comenius University, University Hospital, Bratislava, Slovak Republic;7. Pathological-Anatomical Workplace, Health Care Surveillance Authority, Bratislava, Slovak Republic |
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| Abstract: | Novel therapeutic approaches that address the malignant cells in their stroma microenvironment are urgently needed in lung cancer. The stroma resident mesenchymal stem cells (MSCs) interact with cancer cells in diverse ways including microvesicles (MVs) that transfer proteins and RNA species thereby modulating recipient cells' phenotype. Previously, we have demonstrated that MSCs' secretome from the primary non-small cell lung cancer (NSCLC) niche (lung) and metastatic niche (bone marrow (BM)) demonstrate opposite effects on NSCLC cells in a translation initiation (TI) dependent manner. Here, we examined the effect of MVs secreted from BM-MSCs' or lung-MSCs (healthy, NSCLC) to NSCLC phenotype. Briefly, NSCLC cell lines treated with Lung or BM-MSCs' MVs were assayed for viability (WST-1), cell count/death (trypan), migration (scratch), TI status and MAPKs activation (immunoblotting). Corresponding to previous published trends, Lung-MSCs' MVs promoted NSCLC cells' assayed traits whereas, BM-MSCs' MVs suppressed them. Activation of MAPKs and autophagy was registered in lung-MSCs MVs treated NSCLC cell lines only. Furthermore, lung-MSCs' MVs' treated NSCLC cells demonstrated an early (5 min) activation of MAPKs and TI factors (peIF4E/peIF4GI) not evident in BM-MSCs MVs treated cells. These observations depict a role for MSCs'-MVs in NSCLC phenotype design and display distinct differences between the primary and metastatic niches that correspond to disease progression.In conclusion, the systemic nature of MVs marks them as attractive therapeutic markers/targets and we propose that identification of specific cargoes/signals that differentiate between MSCs MVs of primary and metastatic niches may introduce fresh therapeutic approaches. |
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| Keywords: | NSCLC Mesenchymal stem cells Microvesicles Migration Tumor microenvironment |
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