Application of a Persistent Heparin Treatment Inhibits the Malignant Potential of Oral Squamous Carcinoma Cells Induced by Tumor Cell-Derived Exosomes

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.

Accelerated growth of B16BL6 tumor in mice through efficient uptake of their own exosomes by B16BL6 cells

“…Cancer cell-derived exosomes induce tumor progression both in vitro and in vivo. (29)(30)(31)(32)(33) Significant increase in tumor volume after the intratumoral injection of B16BL6-derived exosomes (Fig. 6a) suggests that these exosomes induced tumor progression.…”

Tumor microenvironment complexity and therapeutic implications at a glance

“…A number of preclinical and clinical findings have reported that targeting pathways and molecules involved in the formation of exosome can inhibit tumor progression, such as heparanase/syndecan-1 axis [182,183] or syndecan heparan sulfate proteoglycans [179,184]. Sento et al reported that heparin may suppress metastasis by lessening the uptake of exosomes, derived from cancer cells in oral squamous cell carcinoma [185]. In addition, Nishida-Aoki and colleagues applied therapeutic antibody targeting EVs including human-specific anti-CD9 or anti-CD63 antibodies which aimed at decreasing tumor-derived exosomes generation, possibly through clearance of EVs by macrophages, resulting in a decline in breast cancer distant metastasis in a mouse model ( Fig.…”

Extracellular vesicles from oral squamous carcinoma cells display pro‐ and anti‐angiogenic properties

“…EVs derived from colorectal carcinoma cells carrying miR‐1246 induce angiogenesis by the activation of SMAD cascade (Yamada et al., ), and EVs derived from renal carcinoma cells expressing CD105, a mesenchymal stem cell marker, not only collaborate with the activation of the angiogenic switch, but also guide tumor growth and metastatic spread (Grange et al., ). Sento, Sasabe, and Yamamoto () have revealed that oral squamous cell carcinoma (OSCC) cells‐derived EVs promoted neoplastic growth and expansion, nonetheless, the events triggered by these vesicles on endothelial cells are still incompletely understood.…”