TGF? 1 In Fibroblasts-derived Exosomes Promotes Epithelial-mesenchymal Transition Of Ovarian Cancer Cells

Background: Cancer-associated fibroblasts(CAF),a major component of the tumor microenvironment,play an important role in interacting with neoplastic cells to promote ovarian cancer progression.Exosomes are nano-sized vesicles that mediate the cross-talk between different cell types.An increasing number of studies have focused on the fact that tumor cell-derived exosomes influence stromal cells.However,the mechanism by which CAF-derived exosomes modulate cancer cells in ovarian cancer remains obscure.Methods: To investigate the role of CAF exosomes in ovarian cancer,we first collected exosomes by serial centrifugation and using different experimental methods to verify our exosomes extraction.Next,we examined the exosomal content of paired primary,metastatic and normal fibroblasts from seven stage IIIC ovarian cancer patients by ELISA.Results: We found that in ovarian CAF-derived exosomes,TGF?1 was upregulated compared to normal omentum fibroblasts(NOF).Exosomes derived from CAF were taken up by ovarian SKOV-3 and CAOV-3 cell lines during co-culture and induced malignant behaviors in cancer cells,including an enhanced migration and invasion ability and the promotion of epithelial-mesenchymal transition(EMT)by activating the SMAD signaling pathway.Besides,exosomes which are rich in TGF?1 could promote the growth of ovarian cancer in in vivo.However,using anti-TGF?1 could inhibit this phenomenon in the orthotopic transplanted tumor model.Conclusions: Our results indicate that the role of TGF?1 in CAF exosomes triggers ovarian cancer cells into a more aggressive phenotype,suggesting that targeting CAF exosomes could be a potential treatment in ovarian cancer.