ABSTRACT
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 (ß-III tubulin) and the number of neurites quantified. To assess innervation in cervical cancer, we immunohistochemically stained cervical cancer patient samples for ß-III 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.
Subject(s)
Afferent Pathways/pathology , Exosomes/pathology , Uterine Cervical Neoplasms/pathology , Afferent Pathways/metabolism , Animals , Cervix Uteri/innervation , Exosomes/metabolism , Female , HeLa Cells , Human papillomavirus 16/isolation & purification , Humans , Immunohistochemistry , Neurites/metabolism , Neurites/pathology , PC12 Cells , Rats , TRPV Cation Channels/metabolism , Tubulin/metabolism , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/virologySubject(s)
Adenocarcinoma of Lung/drug therapy , Antineoplastic Agents/therapeutic use , Cell-Free Nucleic Acids/genetics , Erlotinib Hydrochloride/therapeutic use , Lung Neoplasms/drug therapy , Piperazines/therapeutic use , Acrylamides , Adenocarcinoma of Lung/genetics , Aged , Aniline Compounds , DNA Mutational Analysis , Disease Progression , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/genetics , Polymorphism, Restriction Fragment LengthABSTRACT
Checkpoint inhibitor immunotherapy has recently been proven to be an attractive treatment option for a wide variety of malignancies. Nivolumab, an anti-programmed cell death protein-1 antibody, has been proven effective and safe in treating metastatic renal cell carcinoma (RCC) with a clear cell component. We report the case of a patient with high-grade clear cell RCC with rhabdoid features who has achieved a durable complete response with nivolumab therapy after multiple surgical interventions and progression on pazopanib. Genomic evaluation in this case was characterized in part by a PBRM1 variant, similar to the only other described case of RCC with rhabdoid features obtaining a complete response to nivolumab. This case supports the potential utility of checkpoint inhibitors in aggressive, rare subtypes of RCC where there are limited options for therapy.
