It was indicated that this ratio of CD103+ exosomes in the 17 patients was increased compared with patients with other metastatic carcinoma (Fig. EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis. Conclusions CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. PDE-9 inhibitor CD103+ acted to guide CSC exosomes to target malignancy cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. Graphical abstract ? Electronic supplementary material The online version of this article (10.1186/s12943-019-0997-z) contains supplementary material, which is available to authorized users. was overexpressed in CSC exosomes, and the protein levels of CD103 were significantly higher with M-S-Exo than with S-Exo (Fig. ?(Fig.6e).6e). Furthermore, the flow cytometry results indicated that M-S-Exo contained a higher ratio of CD103+ exosomes (Fig. ?(Fig.6f).6f). To verify the role of CD103 in guiding exosomes to their destination, CD103+ exosomes were removed from total M-S-Exo, and the labeled M-S-Exo and CD103? M-S-Exo were then injected to mice, respectively. Our data exhibited that this CD103+ exosomes-deprived M-S-Exo lost their ability to target tumor and lung, as indicated by abrogation of aggregation of M-S-Exo in tumor and lung after CD103+ exosomes had been removed (Fig. ?(Fig.6g6g & h). Finally, blood samples of CCRCC patients with (Additional?file?1: Table S1) (76) or without (133) metastatic carcinoma were collected and analyzed using flow cytometry for the count CD103+ exosomes. Our results showed that this ratio of CD103+ exosomes over total exsocomes was increased in patients with metastatic carcinoma (Fig. ?(Fig.6i).6i). Of the 133 CCRCC patients, 17 of them had metastasis and died of metastasis within 3?years after surgery. Then, we analyzed the relative ratio of CD103+ exosomes of these 17 patients. We found that the ratio of Rock2 CD103+ exosomes in these 17 patients was present higher level than the other 116 patients without metastasis (Fig. ?(Fig.6j).6j). Moreover, blood samples were detected when the 17 patients present metastasis at the time of diagnosis. It was indicated that this ratio of CD103+ exosomes in the 17 patients was increased compared with patients with other metastatic carcinoma (Fig. ?(Fig.66k). Discussion It PDE-9 inhibitor was reported up to 30% of all renal cell carcinomas have distant metastases at the time of diagnosis. Lung metastases in renal cell carcinoma is the most common among various sites, accounting for 52% of the total [1C3]. More frustratingly, CCRCC patients with metastasis are facing with rather limited therapeutic approaches in the clinic at present. Therefore, it PDE-9 inhibitor is necessary to uncover the intertwined mechanisms behind of metastatic initiation and occurrence of CCRCC and identify efficient therapeutic targets for metastatic CCRCC. In this study, we collected the CSC and cancer exosomes respectively derived from metastatic and non-metastatic CCRCC patients and investigated their relative strengths in conferring the malignancy to tumors. The main findings of the present study can be summarized as following. (1) CSC exosomes were significantly more malignant than cancer exosomes. (2) CSC exosomes strongly promoted EMT thereby the migration and invasion capacities. (3) MiR-19b-3p incorporated into CSC exosomes and transferred by CSC exosomes to cancer cells played the key role in EMT via targeting PTEN. (4) An integrin CD103 enriched in CSC exosomes was a critical determinant of organotropic metastasis of CSC exosomes thereby miR-9b-3p. The larger proportion of CD103+ exosomes PDE-9 inhibitor over total exosomes in CSCs of metastatic patients seemed to be a crucial factor in directing metastatic sites of exosomes (Additional file 2:?Physique S1). Present reports proved that cancer cell population can obtain some properties of CSCs during the EMT process [30, 31]. In our study, CCRCC cells obtained high ability of metastasis via EMT promotion induced by CSCs-derived exosomes, which similarly act as CSCs. CSCs play a key role in tumorigenesis and progression of tumors, and published studies have unraveled the evolving process from CSCs to cancer cells [4]. It is believed that CSCs to drive tumor relapse by re-initiating and repopulating new tumors as a cellular and molecular mechanism for the metastasis of cancer [4, 32]. However, there is still little compelling evidence for CSCs to cause metastasis of cancers via exosomes. The present study shed light on.
