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

ABSTRACT: 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.

SUBMITTER: Pagella P

PROVIDER: S-EPMC7140461 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Pagella Pierfrancesco P Catón Javier J Meisel Christian T CT Mitsiadis Thimios A TA

Cells 20200306 3

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 tumo ...[more]

PMID: 32155948

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Project description:Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1? and tumor necrosis factor-? (TNF?) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic plasticity and nociceptor sensitization are not completely understood. In the present study, we examined the effects of TNF? on neuronal expression of brain-derived neurotrophic factor (BDNF), whose role in synaptic plasticity and sensitization of nociceptive pathways is well documented. We show that 4- and 24-h treatment with TNF? increases BDNF mRNA and protein, respectively, in neuron-enriched dissociated cultures of rat TG. TNF? increases the phosphorylated form of the cyclic AMP-responsive element binding protein (CREB), a transcription factor involved in regulation of BDNF expression in neurons, and activates transcription of BDNF exon IV (former exon III) and, to a lesser extent, exon VI (former exon IV), but not exon I. TNF?-mediated increase in BDNF expression is accompanied by increase in calcitonin gene-related peptide (CGRP), which is consistent with previously published studies, and indicates that both peptides are similarly regulated in TG neurons by inflammatory mediators. The effect of TNF? on BDNF expression is dependent on sodium influx through TTX-sensitive channels and on p38-mitogen-activated protein kinase. Moreover, electrical stimulation and forskolin, known to increase intracellular cAMP, potentiate the TNF?-mediated upregulation of BDNF expression. This study provides new evidence for a direct action of proinflammatory cytokines on TG primary sensory neurons, and reveals a mechanism through which TNF? stimulates de novo synthesis of BDNF in these neurons. Thus, TNF? should be considered in mechanisms of BDNF-dependent neuronal plasticity.

Dataset Information

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

Publications

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

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