Hijacking of Embryonic Programs by Neural Crest-Derived Neuroblastoma: From Physiological Migration to Metastatic Dissemination

Abstract

In the developing organism, complex molecular programs orchestrate the generation of cells in adequate numbers, drive them to migrate along the correct pathways towards appropriate territories, eliminate superfluous cells, and induce terminal differentiation of survivors into the appropriate cell-types. Despite strict controls constraining developmental processes, malignancies can emerge in still immature organisms. This is the case of neuroblastoma (NB), a highly heterogeneous disease, predominantly affecting children before the age of 5 years. Highly metastatic forms represent half of the cases and are diagnosed when disseminated foci are detectable. NB arise from a transient population of embryonic cells, the neural crest (NC), and especially NC committed to the establishment of the sympatho-adrenal tissues. The NC is generated at the dorsal edge of the neural tube (NT) of the vertebrate embryo, under the action of NC specifier gene programs. NC cells (NCCs) undergo an epithelial to mesenchymal transition, and engage on a remarkable journey in the developing embryo, contributing to a plethora of cell-types and tissues. Various NCC sub-populations and derived lineages adopt specific migratory behaviors, moving individually as well as collectively, exploiting the different embryonic substrates they encounter along their path. Here we discuss how the specific features of NCC in development are re-iterated during NB metastatic behaviors.

Neural Networks Recapitulation by Cancer Cells Promotes Disease Progression: A Novel Role of p73 Isoforms in Cancer-Neuronal Crosstalk

“…In line with this, accumulating data indicate that re-expression of genes and/or pathways in the wrong place and at the wrong time offers selective advantages towards acquisition of the metastatic potential. In particular, genes that are normally expressed in anatomical sites other than the site of tumor growth, such as tissue-restricted genes which are normally silent in most tissues [ 4 , 5 ] or genetic programs activated in different developmental/differentiation stages, such as programs of embryonic development [ 6 , 7 ] and human placentation [ 8 ], are reactivated “off-context” in metastatic cells. A universally recognized example is the reactivation of the epithelial–mesenchymal transition (EMT) that controls the neural crest, which gives rise to a variety of vertebrate structures, across several aggressive cancer types (reviewed in [ 9 ]).…”

Molecular targeting therapies for neuroblastoma: Progress and challenges

“…There are some ethnic differences in NB, with the disease being more prevalent in those with European ancestry, and African‐American children tending to exhibit higher‐risk disease 7 . NB tumors have also been classified as an embryonic tumor, because evidence suggests that such tumors originate from neural crest cells (NCCs) during fetal development 8 …”

Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications

“…Interestingly, this event also happens during embryonic development of the sympathetic nervous system as neuroepithelial cells detach from the neural crest. Researchers, therefore, propose that in special cases of NB, a natural BM dissemination can originate from an early mutation event during the migration of neural crest cells [ 92 ].…”