Study Of Mesenchymal Stem Cell-derived Exosomes Induce Differentiation Of Cancer Stem Cell And Overcome Tumor Drug Resistance

Cancer stem cells(CSCs)are a subset of cells in tumor tissues that drive tumorigenesis and development and are resistant to treatment.CSCs have unique self-renewal ability,super differentiation potential and inherent drug resistance,and CSCs play a vital role in the progression,drug resistance,recurrence.At present,the treatment strategy for CSCs is mainly based on"Containment",mainly through chemotherapy,photothermal therapy,photodynamic therapy and other conventional treatment methods to inhibit the proliferation of CSCs and achieve the purpose of treatment.However,some CSCs in tumor tissues will activate self-protection mechanism to avoid damage and form highly resistant malignant CSCs under stimulation and the treatment efficiency is extremely low.Therefore,it is urgent to explore new treatment strategies targeting CSCs.The differentiation status of CSCs determines the malignant degree of tumor to a certain extent.the higher the degree of differentiation of CSCs,the lower the degree of malignancy,or even only benign tumors.At present,the treatment of differentiation of CSCs is mainly through chemical intervention and inhibition of CSCs stemness signaling pathway.Because CSCs share signaling pathways with normal stem cells,treatments that inhibit the differentiation of CSCs’stemness signaling pathways may have side effects on normal stem cells.In addition,residual tumor cells can dedifferentiate to produce new CSCs.Therefore,it is urgent to explore a safe and effective differentiation therapy strategy.The differentiation potential of CSCs is mediated by the tumor microenvironment through the exogenous signals of stromal cells,especially mesenchymal stem cells(MSCs),which are the main mesenchymal cells in the tumor microenvironment and are characterized by multidirectional differentiation,homing and low immunogenicity.When the number of tumor cells is small,MSCs exogenous signaling factors activate CSCs to rapidly proliferate and differentiate into tumor cells.At present,MSC-derived Exosomes have been considered as extracellular vesicles with simple components and mother-parent characteristics,which play an important role in the regulation of CSCs in tumor microenvironment.Therefore,the treatment strategy of MSCs-Exo induced CSCs differentiation combined with chemotherapeutic drug cisplatin provides new ideas and ways to completely eliminate CSCs.Based on this,this project aims to explore the role of MSCs-Exo in inducing the differentiation of CSCs and overcoming tumor resistance.In vitro experiments showed that MSCs-Exo significantly changed the 3D morphology of CSCs and reduced the invasion,migration and xenotransplantation capabilities of CSCs.MSCs-Exo also reduced the expression of stemness marker proteins and stemness genes of CSCs,causing them to lose their"dryness"characteristics.At the same time,MSCs-Exo reduces the expression of CSCs resistance protein and enhances the sensitivity to the chemotherapy drug Cisplatin.Secondly,in vivo experiments show that MSCs-Exo effectively targets tumor tissues and reduces the stemness marker proteins and drug resistance proteins in tumor tissues.Tumor tissues treated by MSCs-Exo effectively reduce tumor drug resistance,and combined cisplatin therapy shows a good anti-tumor effect.Finally,at the molecular level,the mechanism of MSCs-Exo-induced differentiation of CSCs was explored.RT~2 Profiler PCR Array and western blot experiments showed that MSCs-Exo inhibited theβ-catinen and downstream target proteins of CSCs by releasing Dickkopf1protein(DKK-1).These results indicate that MSCs-Exo effectively induces the differentiation of CSCs and reduces the"dryness"of CSCs.Therefore,the safe and effective treatment strategy of MSCs-Exo to induce CSCs differentiation is expected to provide new options for eliminating CSCs and overcoming tumor resistance.