LAUSR

For solid tumors, such as head and neck squamous cell carcinoma (HNSCC), an adequate blood supply is of critical importance for tumor development and metastasis. Tumor-derived exosomes (TEX) accumulate in the tumor microenvironment (TME) and serve as a communication system between tumor and normal stromal cells. This study evaluates in vitro and in vivo effects mediated by TEX that result in promotion of angiogenesis. TEX produced by PCI-13 (HPV−) and UMSCC47 (HPV+) cell lines or from plasma of HNSCC patients were isolated by mini size exclusion chromatography (mini-SEC). TEX morphology, size, numbers, and molecular profile were characterized, and the angiogenesis-inducing potential was measured in arrays and real-time PCR with human endothelial cells (HUVEC). Uptake of labeled TEX by HUVECs was demonstrated by confocal microscopy. Tube formation, proliferation, migration, and adherence by HUVECs in response to TEX were investigated. The 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis mouse model was used to confirm that TEX induce the same results in vivo. TEX were found to be potent inducers of angiogenesis in vitro and in vivo through functional reprogramming and phenotypic modulation of endothelial cells. TEX carried angiogenic proteins and were internalized by HUVECs within 4 hours. TEX stimulated proliferation (P < 0.001), migration (P < 0.05), and tube formation (P < 0.001) by HUVECs and promoted formation of defined vascular structures in vivo. The data suggest that TEX promote angiogenesis and drive HNSCC progression. Future efforts should focus on eliminating or silencing TEX and thereby adding new options for improving existing antiangiogenic therapies. Implications: TEX appear to play an important role in tumor angiogenesis and thus may contribute to tumor growth and metastasis of HNSCC in this context. Mol Cancer Res; 16(11); 1798–808. ©2018 AACR.