Background
Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells.
Methods
The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined.
Results
CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on 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. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker.
Graphical abstract
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Accumulating evidences demonstrate that a population of suppressive cells known as myeloid-derived suppressor cells (MDSCs) is key immune modulators which suppress antitumor immunity. In this study, we found that the level of circulating CD14(+)HLA-DR(-/low) cells in patients was significantly higher than that of healthy donors and was correlated with tumor burden, lymph node metastasis, and tumor, node, and metastasis (TNM) clinical stage. More importantly, we for the first time find the level of CD14(+)HLA-DR(-/low) is a biological indicator of poor prognosis through the analysis of 3-year overall survival. Furthermore, we evidenced that the proportion of CD14(+)HLA-DR(-/low) cells in the tumor metastatic tumor-draining lymph nodes (TDLNs) was notably higher compared to tumor-free TDLNs. Additionally, CD14(+)HLA-DR(-/low) cells from esophageal squamous cell carcinoma (ESCC) patients expressed dramatically increased programmed death ligand 1 (PD-L1) comparing to that from healthy control. Subsequently, blocking PD-L1 pathway by antibody could effectively reverse the suppressive effect on autologous T cell proliferation mediated by CD14(+)HLA-DR(-/low) cells in vitro. In conclusion, our data revealed CD14(+)HLA-DR(-/low) MDSCs which increase in ESCC patients is a novel poor prognostic indicator and may exert immunosuppressive properties through PD-L1/PD-1 pathway.
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