Abstract
Recently, exosomes secreted by menstrual mesenchymal stem cells have been identified as inhibitory agents of tumor angiogenesis and modulators of the tumor cell secretome in prostate and breast cancer. However, their direct effect on endothelial cells and paracrine mediators have not yet been investigated. Using a carrier-based cell culture system to test the scalability for exosome production, we showed that different types of endothelial cells present specific kinetics for exosomes internalization. Exosome-treatment of endothelial cells increased cytotoxicity and reduced VEGF secretion and angiogenesis in a dose-dependent manner. Using the hamster buccal pouch carcinoma as a preclinical model for human oral squamous cell carcinoma, we demonstrated a significant antitumor effect of intra-tumoral injection of exosomes associated with a loss of tumor vasculature. These results address up-scaling of exosome production, a relevant issue for their clinical application, and also assess menstrual stem cell exosomes as potential anti-angiogenic agents for the treatment of neoplastic conditions.
Highlights
Head and neck cancer, with oral squamous cell carcinoma as its major subtype, ranks among the ten most common cancer types worldwide[1]
In order to test whether the observed anti-angiogenic effect was mesenchymal stem cell (MenSC)-specific, we examined the effect of UCMSC-exosomes and dermal fibroblast exosomes on Human umbilical cord vein endothelial cells (HUVEC) cells as shown in supplementary Fig S6
In the case of p53, the fold change was 1.08 ± 0.34 and in the case of Ki67 0.73 ± 0.23. It is well-known that the therapeutic effects of stem cell therapy are in large proportion caused by their secreted factors. These paracrine mechanisms have been linked to exosomes[42,43], membrane-enclosed nanovesicles that shuttle biomolecular cargoes that can effectively alter the biological properties of target cells[44]
Summary
With oral squamous cell carcinoma as its major subtype, ranks among the ten most common cancer types worldwide[1]. The fact that MenSC-exosomes show diverse effects on specific tumor types underscores the importance of studying the different cancer cell types to determine the scope of possible exosome-based treatments. Adherent cells are mostly grown in 2D culture on plastic dishes or flasks From this manufacturing process a limited quantity of exosomes is obtained - a fact that complicates translation of exosome treatments into the clinic. We studied the biological effect of the obtained MenSC-exosomes on endothelial cells in vitro and assessed the effect of exosome treatment on angiogenesis and tumor growth in vivo using the hamster buccal pouch (HBP) carcinoma model - a preclinical model that closely mimics the human OSCC30. This work provides relevant information about an anti-angiogenic therapy based on MenSC-exosomes and demonstrates for the first time the cytotoxic effect they exert on endothelial cells in vitro as well as a reduction of the tumor vasculature and tumor growth in vivo
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