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

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Review

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

Céline Delloye-Bourgeois et al. Front Mol Neurosci.

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.

Keywords: embryogenesis; metastasis; migration and development; neural crest; neuroblastoma.

Figures

Figure 1
Figure 1
Microenvironment-driven guidance of trunk neural crest cells (NCCs) along defined migration pathways. Left: schematic view of neural crest (NC) subtypes along the rostro-caudal embryonic axis. Relevant somites to delimit NC populations are numbered on the scheme. Right: transverse section schematic view of trunk NCCs successive waves of migration, figured with blue arrows. Receptors involved in NCCs guidance interaction with environmental cues are listed for each pathway. Examples of environmental cues produced by key structural choice points are mentioned (in red, repulsive cues; in green, attractive cues). From the dermamyotome: Slit2, Draxin and Sema3A; from the posterior sclerotome: CXCL12, Sema3F and EphrinB1/2; from the Notochord and forelimb: Sema3A; from the intersomitic vessels: artemin; from the para-aortic mesenchyme: CXCL12 and neuregulin1 (NRG1). AM, adrenal medulla; DA, dorsal aorta; dm, dermamyotome; DRG, dorsal root ganglia; isv, intersomitic vessel; Me, mesonephros; NT, neural tube; Me, mesonephros; No, notochord; pSG, primary sympathetic ganglia; scl, sclerotome; SG, sympathetic ganglion.
Figure 2
Figure 2
Trunk NCCs collective migration strategy. Collective migration of trunk NCCs figured as the result of combined environmental influences (environmental force, 1) and NCC population intrinsic influences (NCCs “population-autonomous” forces). The latter encompass a co-attraction mechanism (2) led by C3a ligand/receptor co-expression within the NCC stream and contact inhibition of locomotion (CIL; 3) ensuring NCCs migration stop and repolarization upon cell-cell collision. These mechanisms act in concert to drive a supracellular organization and migration of the NCCs stream.
Figure 3
Figure 3
Schwann cells precursor (SCP) migration strategy, example of SCPs supplying the adrenal medulla (AM) with chromaffin cell precursors. Left: schematic view of embryonic closely related sympathetic chain and connected peripheral nerves, DA, and ribs. Right: transverse section schematic view of SCPs emerging from the NC and undergoing perineural migration to reach the AM as a final target. NRG1/ERBB ligand/receptor in trans interaction is presented as a hypothetic signaling mediating SCPs/nerve interaction.
Figure 4
Figure 4
Sympatho-adrenal NCCs (SA-NCCs) and SCPs contributions to the bone marrow (BM) niche. Schematic representation of NC main contributions to the BM niche. SA-NCCs addressed next to the ventral portion of the aorta induce the hematogenous ventral aortic endothelium to generate HSCs, an induction that might involve catecholamines produced by SA-NCCs. Emerging HSCs then colonize the BM niche via the blood circulation. The second described mechanism resides in NCCs-derived SCPs that colonize the BM niche via perineural migration on sympathetic nerves that innervate the niche. SCPs then give rise to Nestin+-MSCs that mainly sustain HSCs by secreting CXCL12 cue.
Figure 5
Figure 5
NCCs/SCPs migratory strategies potentially used or hijacked by neuroblastoma (NB) cells. NB cells are able to engage a physiological trunk NCCs-like collective migratory behavior that address them to sympatho-adrenal derivatives where they coalesce and form primary tumors (1). Within the primary tumor, NB cells preparing for secondary dissemination switch towards SCPs-like (2a) and/or NCCs-driven HSCs-like (2b) migratory behaviors that would allow them colonizing secondary foci such as the BM niche by hijacking peripheral nerves and aorta major migratory highways. Such mechanisms could explain the rapid, extensive and concomitant emergence of metastatic foci in young children affected by the disease.

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    Uemura S, Ishida T, Thwin KKM, Yamamoto N, Tamura A, Kishimoto K, Hasegawa D, Kosaka Y, Nino N, Lin KS, Takafuji S, Mori T, Iijima K, Nishimura N. Uemura S, et al. Front Oncol. 2019 Jun 4;9:455. doi: 10.3389/fonc.2019.00455. eCollection 2019. Front Oncol. 2019. PMID: 31214500 Free PMC article. Review.

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