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.

Ameloblastoma: clinical presentation, multidisciplinary management and outcome

“…Ameloblastoma cells can also express markers of dental epithelial stem cells (i.e. SOX2 and BMI1), and therefore, they have the potential to transdifferentiate into cancer stem cells and subsequently be responsible for tumor relapse [ 27 ]. The fragmentation of primary tumors during conservative surgical procedures resulting in the seeding of ameloblastoma cells on wound beds may also contribute to increasing the recurrence risk [ 13 ].…”

Expression of stem cell markers in stroma of odontogenic cysts and tumors

“…" 24 Accordingly, at appropriate levels of expression, it generates a cellular state that can respond to microenvironmental needs, thus conferring SOX2‐expressing cells the ability to differentiate downwards defined lineages, mostly of neural differentiation 25 . In this context, it has been shown that the stromal cells in AMB expressing P75NTR, 3 another stem cell marker also related to neural differentiation, together with stromal fibroblasts expressing the stem cell marker CD90, may affect the aggressiveness of this tumor 26 . An additional level of action of SOX2 is promotion of tumor aggressiveness and the process of epithelial‑mesenchymal transition (EMT) in several types of cancers, like in tongue squamous cell carcinoma 27 .…”

“…Stem cells confer tissues the potential for repair and regeneration and also tumorigenic properties 1 . Apparently, dental tissues 2 and related lesions 3 are not an exception. Octamer‐binding transcription factor 4 (Oct4), Nanog, and sex‐determining‐region‐Y‐box2 (SOX2) are considered as core transcription factors necessary for pluripotency in embryonal stem cells and are known to act as either transcriptional activators or repressors and share a substantial fraction of their target genes 1 .…”

Bioengineered tooth emulation systems for regenerative and pharmacological purposes

“…Co-cultures of trigeminal ganglia with embryonic and postnatal teeth in microfluidic chips faithfully reproduced the in vivo situation, for example innervation was constantly repealed over several days of culture by embryonic teeth, while it was promoted and attracted by postnatal teeth (Pagella et al, 2014b). Then, this chip was employed to study the neurotrophic properties of ameloblastomas (Pagella et al, 2020a) as well as to compare the neurotrophic properties of hDPSCs and human bone marrow stem cells, showing that www.ecmjournal.org hDPSCs induce the growth of significantly longer axons as well as the formation of extensive neuronal networks (Pagella et al, 2020b). In this case, narrow grooves between the channels allow only axons to pass and establish a connection between the compartments (Fig.…”