Mechanisms Of Carcinoma-associated Fibroblast Derived Exosomes Inducing Dedifferentiation Of Colorectal Cancer Cells And Promoting Tumor Invasion And Metastasis

Cancer stem cells are closely related to invasion and metastasis of colorectal cancers,while the exact mechanism of the increasing number and cell-of-origin of CSCs remains unclear.Carcinoma-associated fibroblasts(CAFs)are associated with metastasis and recurrence of colorectal cancers.Tumor invasion and metastasis can be significantly inhibited by elimination of CAFs.Our study investigated the role of CAFs in inducing dedifferentiation of colorectal cancer cells into CSCs and promoting tumor cell invasion and metastasis.We first demonstrated that co-culture with CAFs could alter the morphology of colorectal cancer cells and enhance the invasion,metastasis and ahesion ability and cell sternness of tumor cells in a paracrine manner.These paracrine effects of CAFs on tumor cells were through exosomes.Exosomes derived from CAFs promoted tumor invasion and metastaisis and increased the number of CSCs both in vitro and in vivo.Inhibiting exosomes secretion blocked the effects.Then we sorted colorectal cancer cells with CSCs surface marker,CD133 into CSCs(CD133-/lo)and non-CSCs(CD133+/hi)and treated them with CAFs-exosomes.CAFs-exosomes induced dedifferentiation of CD133-/lo into CSCs and sustained stem cell phenotype of CD133+/hi.They also promoted endothelial interstitial transformation(EMT)of CSCs,thus enhanced tumor invasion and metastasis.We further identified a highly expressed microRNA,miRNA21-5p in CAFs-exosomes by MicroArray.GO,KEGG and TargetScan databases analyses indicated that miRNA21-5p may exert effects on cancer cells through regulating YAP1.Our findings revealed the important role of exosomes in cancer therapy.Inhibiting exosomes secretion of CAFs in tumor treatment will bring more benefits for patients.