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Open AccessArticle

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

1
Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland
2
Department of Anatomy and Embryology, Faculty of Medicine, University Complutense Madrid, 28040 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(3), 644; https://doi.org/10.3390/cells9030644
Received: 11 February 2020 / Revised: 4 March 2020 / Accepted: 5 March 2020 / Published: 6 March 2020
(This article belongs to the Special Issue Stem Cell Therapy in Oral and Maxillofacial Region)
Ameloblastomas are locally invasive and aggressive odontogenic tumors treated via surgical resection, which results in facial deformity and significant morbidity. Few studies have addressed the cellular and molecular events of ameloblastoma onset and progression, thus hampering the development of non-invasive therapeutic approaches. Tumorigenesis is driven by a plethora of factors, among which innervation has been long neglected. Recent findings have shown that innervation directly promotes tumor progression. On this basis, we investigated the molecular characteristics and neurotrophic properties of human ameloblastomas. Our results showed that ameloblastomas express dental epithelial stem cell markers, as well as components of the Notch signaling pathway, indicating persistence of stemness. We demonstrated that ameloblastomas express classical stem cell markers, exhibit stem cell potential, and form spheres. These tumors express also molecules of the Notch signaling pathway, fundamental for stem cells and their fate. Additionally, we showed that ameloblastomas express the neurotrophic factors NGF and BDNF, as well as their receptors TRKA, TRKB, and P75/NGFR, which are responsible for their innervation by trigeminal axons in vivo. In vitro studies using microfluidic devices showed that ameloblastoma cells attract and form connections with these nerves. Innervation of ameloblastomas might play a key role in the onset of this malignancy and might represent a promising target for non-invasive pharmacological interventions. View Full-Text
Keywords: ameloblastoma; oral cancers; cancer stem cells; SOX2; innervation; neurotrophins; notch signaling; trigeminal neurons; neuronal contacts; microfluidic devices ameloblastoma; oral cancers; cancer stem cells; SOX2; innervation; neurotrophins; notch signaling; trigeminal neurons; neuronal contacts; microfluidic devices
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Pagella, P.; Catón, J.; Meisel, C.T.; Mitsiadis, T.A. Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons. Cells 2020, 9, 644.

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