From Neural Crest Development to Cancer and Vice Versa: How p75NTR and (Pro)neurotrophins Could Act on Cell Migration and Invasion?

Abstract

The p75 neurotrophin receptor (p75NTR), also known as low-affinity nerve growth factor, belongs to the tumor necrosis factor family of receptors. p75NTR is widely expressed in the nervous system during the development, as well as, in the neural crest population, since p75NTR has been described as ubiquitously expressed and considered as a neural crest marker. Neural crest cells (NCCs) constitute an transient population accurately migrating and invading, with precision, defined sites of the embryo. During migration, NCCs are guided along distinct migratory pathways by specialized molecules present in the extracellular matrix or on the surfaces of those cells. Two main processes direct NCC migration during the development: (1) an epithelial-to-mesenchymal transition and (2) a process known as contact inhibition of locomotion. In adults, p75NTR remains expressed by NCCs and has been identified in an increasing number of cancer cells. Nonetheless, the regulation of the expression of p75NTR and the underlying mechanisms in stem cell biology or cancer cells have not yet been sufficiently addressed. The main objective of this review is therefore to analyze elements of our actual knowledge regarding p75NTR roles during the development (mainly focusing on neural crest development) and see how we can transpose that information from development to cancer (and vice versa) to better understand the link between p75NTR and cell migration and invasion. In this review, we successively analyzed the molecular mechanisms of p75NTR when it interacts with several coreceptors and/or effectors. We then analyzed which signaling pathways are the most activated or linked to NCC migration during the development. Regarding cancer, we analyzed the described molecular pathways underlying cancer cell migration when p75NTR was correlated to cancer cell migration and invasion. From those diverse sources of information, we finally summarized potential molecular mechanisms underlying p75NTR activation in cell migration and invasion that could lead to new research areas to develop new therapeutic protocols.

Neuroblastoma—A Neural Crest Derived Embryonal Malignancy

“…Also, RhoA, Rac1 and Cdc42 have been implicated in both Eph/ephrin internalization and signaling. Eph/ephrin signaling plays essential roles during migration of neural crest cells, such as cytoskeleton remodeling and axon guidance but also stimulate angiogenesis and tissue separation (Baker and Antin, 2003; Xu and Wilkinson, 2013; Wislet et al, 2018). High expression levels of Ephb6 and its ligand ephrin-B2 and ephrin-B3 is associated with low-stage neuroblastoma (Tang et al, 2000).…”

Neurogenesis From Neural Crest Cells: Molecular Mechanisms in the Formation of Cranial Nerves and Ganglia

“…An efficient method was described for the generation of NCCs from human pluripotent stem cells through the sustained activation of Wnt signaling combined with low Smad signaling, accomplished by the inhibition of the Activin/Nodal pathway. After 12 days, this constant inhibition of Smad considerably inhibited the formation of CNS Pax6 (OMIM 607108)-positive cells and increased the percentage of cells positive for the low affinity neurotrophin receptor, p75 NTR , which is expressed in the migratory NC (Heuer et al, 1990;Wislet et al, 2018). Within the population of p75 positive cells, authors found cells with intermediate levels of p75, but positive for Pax6; in contrast, the cell population that expresses high levels of p75 was positive for Ap-2α (OMIM 107580), characteristic of NCCs (Menendez et al, 2011).…”

Decoding the Role of CD271 in Melanoma

“…NCSCs delaminate from the neuroepithelium by epithelial-to-mesenchymal transition (EMT) and migrate along body axes. Migrating neural crest (NC) cells lose the expression of E-cadherin (CDH1) and gain expression of human natural killer-1 (HNK1)/3-beta-glucuronosyltransferase 1 (B3GAT1), CD271, and endothelin receptor type B (EDNRB) [ 13 , 14 ] ( Figure 1 a). The expression of CD271 enables the tracking of NCSCs during early human NC development and the isolation of multiple NCSCs from mammalian fetal peripheral nerve and differentiated human embryonic stem cells (hESCs) [ 12 , 13 , 15 ].…”

“…First insight into the functional role of CD271 in cell migration was provided by murine models, which enabled the conditional knockout of CD271 in NC cells. The latter revealed a decrease in the sciatic nerve diameter and a deficiency of hematopoiesis, reviewed by Wislet et al [ 14 ]. Although the role of CD271 during melanocyte development and specification ( Figure S1a , comprehensively reviewed by Douarin et al, White et al and Blake et al [ 19 , 24 , 25 ] is unknown, knockdown studies in melanoma revealed a close relationship of CD271 with FOXD3, SOX2, and SOX10.…”

“…In addition, the association of CD271 with tropomyosin-related kinases (TRKs) results in the generation of high-affinity neurotrophin binding sites and mediates cell survival in a mitogen-activated kinase (MAPK)-dependent manner via adaptor proteins SHC, GRB2, and SOS ( Figure 4 , second panel). Besides MAPK signaling, the CD271/TRK heterodimers signal trough PI3K and PLCγ [ 14 ]. Sortilin (SORT1), belongs to the vacuolar protein sorting 10 family (Vps10) and is mainly found within late endosomes derived from the trans-golgi network, controlling the anterograde trafficking of neurotrophin receptors and secretion of pro-BDNF [ 96 ].…”