Innervation of cervical carcinoma is mediated by cancer-derived exosomes

Objective. Recently, our laboratory identified sensory innervation within head and neck squamous cell carcinomas (HNSCCs) and subsequently defined a mechanism whereby HNSCCs promote their own innervation via the release of exosomes that stimulate neurite outgrowth. Interestingly, we noted that exosomes from human papillomavirus (HPV)-positive cell lines were more effective at promoting neurite outgrowth than those from HPV-negative cell lines. As nearly all cervical tumors are HPV-positive, we hypothesized that these findings would extend to cervical cancer. Methods. We use an in vitro assay with PC12 cells to quantify the axonogenic potential of cervical cancer exosomes, PC12 cells are treated with cancer-derived exosomes, stained with the pan-neuronal marker (13-III tubulin) and the number of neurites quantified. To assess innervation in cervical cancer, we immunohistochemically stained cervical cancer patient samples for i3-Ill tubulin and TRPV1 (sensory marker) and compared the staining to normal cervix. Results. Here, we show the presence of sensory nerves within human cervical tumors. Additionally, we show that exosomes derived from HPV-positive cervical cancer cell lines effectively stimulate neurite outgrowth. Conclusions. These data identify sensory nerves as components of the cervical cancer microenvironment and suggest that tumor- derived exosomes promote their recruitment. (C) 2019 The Authors. Published by Elsevier Inc.