Abstract
Exosomes are 30–100 nm-sized membranous vesicles, secreted from a variety of cell types into their surrounding extracellular space. Various exosome components including lipids, proteins, and nucleic acids are transferred to recipient cells and affect their function and activity. Numerous studies have showed that tumor cell-derived exosomes play important roles in tumor growth and progression. However, the effect of exosomes released from oral squamous cell carcinoma (OSCC) into the tumor microenvironment remains unclear. In the present study, we isolated exosomes from OSCC cells and investigated the influence of OSCC cell-derived exosomes on the tumor cell behavior associated with tumor development. We demonstrated that OSCC cell-derived exosomes were taken up by OSCC cells themselves and significantly promoted proliferation, migration, and invasion through the activation of the PI3K/Akt, MAPK/ERK, and JNK-1/2 pathways in vitro. These effects of OSCC cell-derived exosomes were obviously attenuated by treatment with PI3K, ERK-1/2, and JNK-1/2 pharmacological inhibitors. Furthermore, the growth rate of tumor xenografts implanted into nude mice was promoted by treatment with OSCC cell-derived exosomes. The uptake of exosomes by OSCC cells and subsequent tumor progression was abrogated in the presence of heparin. Taken together, these data suggest that OSCC cell-derived exosomes might be a novel therapeutic target and the use of heparin to inhibit the uptake of OSCC-derived exosomes by OSCC cells may be useful for treatment.
Highlights
Oral cancer accounts for 2%–3% of all human malignancies and is trending upward yearly [1]
The effects of Oral squamous cell carcinoma (OSCC) cell-derived exosomes on migration and invasion were partially abolished by the addition of these inhibitors (Fig 5B and 5C). These results suggest that OSCC cell-derived exosomes promote tumor cell proliferation, migration, and invasion of OSCC cells through activation of the Akt, ERK, and JNK signaling pathways
These results suggest that continuous administration of heparin is needed to inhibit tumor progression induced by OSCC cell-derived exosomes
Summary
Oral cancer accounts for 2%–3% of all human malignancies and is trending upward yearly [1]. Tumor cell-derived exosomes may promote tumor progression by exhibiting immunosuppressive properties, facilitating tumor invasion and metastasis, stimulating tumor cell proliferation, or inducing drug resistance [8, 16,17,18,19,20]. These contradictory findings lead us to examine the exact function of OSCC cell-derived exosomes in cancer development. OSCC cell treatment with heparin inhibited exosome uptake by recipient cells as well as tumor growth and progression induced by OSCC cell-derived exosomes in vitro and in vivo. The results of the present study provide novel therapeutic strategies, targeting OSCC cell-derived exosomes critical for OSCC growth and progression
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