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Background Exosomes are nano-sized biological vesicles released by many kinds of cells, which play an important role in tumor metastasis through transporting cytokines, RNAs and proteins. However, the molecular mechanisms of exosomes in hepatocellular carcinoma (HCC) metastasis are not completely understood. Materials and methods Exosomes derived from hepatoma cell lines with different invasion characteristics. Exosome characteristics, cell migration and invasion, and effects on major signal transduction pathways deregulated in cancer cells were analyzed by transmission electron microscopy (TEM), wound-healing assay, Trans-well invasion assay and Western blot-based assays, respectively. Moreover, exosomes effects on tumor metastasis in vivo were investigated by subcutaneous transplantation tumor model of athymic nude mice. Results Exosomes derived from hepatoma cells can promote the migration and invasion of recipient cells, induce the decrease of E-cadherin expression, increase the expression of Vimentin and promote epithelial-mesenchymal transition (EMT) in cells. Moreover, highly invasive hepatoma-cells-derived exosomes effects are stronger than low-invasive hepatoma cells and normal liver cells exosomes. Mechanistic studies showed that the biological alterations in recipient HCC cells treated with MHCC97H and MHCC97L-derived exosomes were caused by inducing EMT via TGF-β/Smad signaling pathway. In vivo experiments also suggest that highly invasive hepatoma cells derived exosomes are more likely to promote lung metastasis of HCC in nude mice. Conclusion Our results reveal the important role of tumor-derived exosomes in the migration and invasion of recipient cells and exosomes may be the novel therapeutic and prognostic targets for HCC patients.

Zhen Qu,1,* Jiawei Feng,1,* Hua Pan,2 Yong Jiang,1 Yunfei Duan,1 Zhenzhong Fa31Department of Hepatopancreatobiliary Surgery, The First People’s Hospital of Changzhou, the Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, People’s Republic of China; 2Department of Hepatobiliary Surgery, The People’s Hospital of Liyang, Liyang, Jiangsu, People’s Republic of China; 3Department of Hepatobiliary Surgery, Changzhou Wujin People’s Hospital, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Yunfei DuanDepartment of Hepatopancreatobiliary Surgery, The First People’s Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, People’s Republic of ChinaEmail 605035098@qq.comZhenzhong FaDepartment of Hepatobiliary Surgery, Changzhou Wujin People’s Hospital, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, People’s Republic of ChinaEmail wjphfzz@126.com*These authors contributed equally to this workBackground: Exosomes are nano-sized biological vesicles released by many kinds of cells, which play an important role in tumor metastasis through transporting cytokines, RNAs and proteins. However, the molecular mechanisms of exosomes in hepatocellular carcinoma (HCC) metastasis are not completely understood.Materials and methods: Exosomes derived from hepatoma cell lines with different invasion characteristics. Exosome characteristics, cell migration and invasion, and effects on major signal transduction pathways deregulated in cancer cells were analyzed by transmission electron microscopy (TEM), wound-healing assay, Trans-well invasion assay and Western blot-based assays, respectively. Moreover, exosomes effects on tumor metastasis in vivo were investigated by subcutaneous transplantation tumor model of athymic nude mice.Results: Exosomes derived from hepatoma cells can promote the migration and invasion of recipient cells, induce the decrease of E-cadherin expression, increase the expression of Vimentin and promote epithelial-mesenchymal transition (EMT) in cells. Moreover, highly invasive hepatoma-cells-derived exosomes effects are stronger than low-invasive hepatoma cells and normal liver cells exosomes. Mechanistic studies showed that the biological alterations in recipient HCC cells treated with MHCC97H and MHCC97L-derived exosomes were caused by inducing EMT via TGF-β/Smad signaling pathway. In vivo experiments also suggest that highly invasive hepatoma cells derived exosomes are more likely to promote lung metastasis of HCC in nude mice.Conclusion: Our results reveal the important role of tumor-derived exosomes in the migration and invasion of recipient cells and exosomes may be the novel therapeutic and prognostic targets for HCC patients.Keywords: HCC, exosomal, TGF-β, EMT, tumor metastasis

The floor field model has been widely used in evacuation simulation research based on cellular automata model. However, conventional methods of setting floor field will lead to highly insufficient utilization of the exit area when people gather on one side of the exit. In this study, an extended cellular automata model with modified floor field is proposed to solve this problem. Additionally, a congestion judgment mechanism is integrated in our model, whereby people can synthetically judge the degree of congestion and distance in front of them to determine whether they need to change another exit to evacuate or not. We contrasted the simulation results of the conventional floor field model, the extended model proposed in this paper, and Pathfinder software in a same scenario. It is demonstrated that this extended model can ameliorate the problem of insufficient utilization of the exit area and the trajectory of pedestrian movement and the crowd shape of pedestrians in front of exit in this new model are more realistic than those of the other two models. The findings have implications for modeling pedestrian evacuation.