Cell. Mol. Life Sci. DOI 10.1007/s00018-017-2685-8 Cellular and Molecular LifeSciences REVIEW WNT signaling, the development of the sympathoadrenal–paraganglionic system and neuroblastoma Jürgen Becker1 · Jörg Wilting1 Received: 6 July 2017 / Revised: 22 September 2017 / Accepted: 11 October 2017 © The Author(s) 2017. This article is an open access publication Abstract Neuroblastoma (NB) is a tumor of the sympa- Abbreviations thoadrenal system arising in children under 15 years of age. ALK Anaplastic lymphoma kinase In Germany, NB accounts for 7% of childhood cancer cases, BMP Bone morphogenetic protein but 11% of cancer deaths. It originates from highly migra- DBH Dopamine beta-hydroxylase tory progenitor cells that leave the dorsal neural tube and DKK Dickkopf (WNT signaling pathway contribute neurons and glial cells to sympathetic ganglia, inhibitor) and chromafn and supportive cells to the adrenal medulla FOXO Forkhead box protein o transcription factor and paraganglia. Clinically, histologically and molecu- FZD Frizzled (G protein-coupled) receptor larly, NBs present as extremely heterogeneous, ranging GSK3β Glycogen synthase kinase 3β from very good to very poor prognosis. The etiology of NB ILK Integrin-linked kinase still remains unclear and needs to be elucidated, however, LGR4/5 Leucine-rich repeat-containing G protein- aberrant auto- and paracrine embryonic cell communica- coupled receptor 4/5 tions seem to be likely candidates to initiate or facilitate the MDR1 Multidrug resistance protein 1 emergence, progression and regression of NB. The wingless- NB(s) Neuroblastoma(s) type MMTV integration site (WNT) family of proteins rep- NC Neural crest resents an evolutionary highly conserved signaling system Neuro2a Mouse-derived neuroblastoma cell line that orchestrates embryogenesis. At least 19 ligands in the NGF Nerve growth factor human, numerous receptors and co-receptors are known, NOG Noggin which control not only proliferation, but also cell polarity, NT3 Neurotrophin-3 migration and diferentiation. Here we seek to interconnect PTK7 Protein tyrosine kinase 7 aspects of WNT signaling with sympathoadrenal and para- ROR1/2 Receptor tyrosine kinase-like orphan ganglionic development to defne new WNT signaling cues receptor-1/-2 in the etiology and progression of NB. R-spondin-1 Secreted protein, interacts with WNT4 RYK Related to receptor tyrosine kinase Keywords Neuroblastoma · Sympathoadrenal system · SFRP1 Secreted frizzled-related protein 1 Paraganglion · Neural crest SOX Sry-related HMG box transcription factor TCF/LEF T-cell factor/lymphoid enhancer factor (transcription factor) TGFBI Transforming growth factor-induced pro- tein h3 = Keratoepithelin, Bigh3 TH Tyrosine hydroxylase * Jürgen Becker TNKS1 Tankyrase1 [email protected]‑goettingen.de TRK-A Tyrosine (tropomyosin) receptor kinase-A 1 Institute of Anatomy and Cell Biology, University Medical School Göttingen, 37075 Göttingen, Germany Vol.:(0123456789)1 3 J. Becker, J. Wilting VANGL2 Van-gogh-like-2 MYCN is the strongest indicator for highly malignant and WNT Wingless-type MMTV integration site therapy-resistant NB. Despite initially successful therapy, family these patients frequently sufer from relapse, and die because of metastasis formation and resistance to chemotherapy (reviewed by [14]). However, although MYCN amplifcation Neuroblastoma is a potent predictor of disease outcome, it afects only about 25% of the patients, illustrating the urgent need for new diag- Neuroblastoma (NB) is a tumor of the sympathetic nervous nostic markers and therapeutic targets in NB. Thereby, inter- system that arises in children under 15 years of age with a disciplinary approaches combining developmental biology frequency of 1:5700. In Germany, NB accounts for 7% of and pediatric oncology of the sympathoadrenal system have childhood cancer cases, but is responsible for approx. 11% been published in the past 50 years, and may still provide of cancer deaths in children [1]. It originates from highly novel hints for new molecular targets for diagnosis and treat- migratory, sympathoadrenal progenitor cells from the neu- ment of NB [15–20]. ral crest that migrate long distances and form the adrenal medulla, paraganglia, as well as paravertebral and preverte- bral sympathetic ganglia (for review see: [2, 3]). It is com- monly accepted to refer to NB as an embryonic tumor [1, The sympathoadrenal–paraganglionic system 3], which becomes evident when looking at the patient’s age. Approximately 45% of NBs are diagnosed at birth or In the embryo, the sympathoadrenal system consists of the within the frst years of life, with a median age at diagnosis sympathetic nervous system, the adrenal medulla and func- of 1.2 years. Even more strikingly, at the age of 10 years, tionally related paraganglia. Unfortunately, the term para- more than 98% of NBs have been presented clinically [1]. ganglion is often also used for glomera, such as the Glomus Histologically and clinically, NBs present heterogeneously, caroticum and the Glomera aortica, which are located along spanning from poorly diferentiated, highly proliferative, the glossopharyngeal and vagal nerves, and represent sen- metastasizing and chemotherapy-resistant tumors with unfa- sory organs (pCO2, pO2, pH). They should not be mixed up vorable prognosis to localized, well-diferentiated, Schwann with the sympathoadrenal–paraganglionic system, despite cell stroma-rich tumors with good response to mild chemo- their common origin from the neural crest [21]. Paraganglia, therapy or diferentiating agents such as retinoic acid, and which are usually located in the retro-peritoneal region are excellent prognosis (reviewed by [4–6]). endocrine organs, which increase the embryos cardiac output Classically, NB are staged into fve groups (1–4, and under hypoxia (e.g., cigarette smoking of mother) by secre- 4S) according to localization, lymph node involvement, tion of catecholamines. They usually regress during early and metastasis formation [7, 8]. Currently, classifcation is years after birth. about to change into a system considering a variety of risk factors, with the aim to facilitate the comparison of diferent – The sympathetic nervous system has two neuronal levels. national studies. Here, the risk groups are divided into L1, The preganglionic, the so-called “frst” neurons of the L2, M and MS [5, 9]. However, both systems emphasize the sympathetic nervous system are located in the (mainly special signifcance of tumors in children up to 18 months thoracic) lateral spinal medulla of segments C8–L2/3. of age. These NBs are grouped into the 4S or MS stage, These neurons are not involved in NB development, as respectively, taking into account that despite metastases to their synaptic transmitter acetylcholine is not found in skin, liver, and to a low extend, also to bone marrow, these NB, and primary NB is never localized in the central tumors are in most cases well curable by mild chemotherapy nervous system. The “second” neuron is located in the and application of diferentiating agents such as retinoids [4, para-vertebral ganglia of the sympathetic trunk, pre- 10]. In general, localized tumors in young patients are highly vertebral ganglia, and pelvic sympathetic ganglia. It is prone to spontaneous diferentiation and regression. As only referred to as postganglionic, which means the axons of a small percentage of these tumors progresses to metastatic these neurons leave the ganglion towards target organs. stages, medical intervention is no longer regarded as the frst – In the adrenal medulla, chromafn, adrenergic (approx. choice, instead observation and waiting (“wait and see”) may 75%) and noradrenergic (approx. 25%) cells are inner- be sufcient [11]. The basis for this type of tumor behavior vated by pre-ganglionic cholinergic neurons [16]. In seems to reside in a natural regression of sympathoadrenal addition, the adrenal medulla hosts small groups of tissue starting at 18 months of age [12, 13]. post-ganglionic neurons, as well as glia-like cells (sus- Even though a multitude of molecules have been found to tentacular cells), and may therefore be considered a dual infuence NB behavior and may help to predict the outcome, sympathetic ganglion [22–25]. Interestingly, this is the amplifcation and/or over-expression of the proto-oncogene location where the majority of primary NBs develop [3]. 1 3 WNT signaling, the development of the sympathoadrenal–paraganglionic system and neuroblastoma – Post-ganglionic sympathetic neurons use noradrenalin as their transmitter, the closely related chromafn cells produce (nor)adrenalin for endocrine purposes. The only exception are the sympathetic axons that supply the der- mal sweat glands, which are cholinergic [26]. Homovan- illic acid and vanillylmandelic acid are degradation prod- ucts of catecholamines, and they are commonly found enriched in the urine of NB patients [27]. These facts, together with further molecular hints that will be discussed later, point out to the sympathoadre- nal–paraganglionic origin of NB. During embryonic devel- opment, the precursor cells of the sympathoadrenal system delaminate from the dorsal neural tube and form the neural crest (Fig. 1). Embryonic development of the sympathoadrenal– paraganglionic system Regarding NB as an embryonic tumor, it is of interest that the progenitors of postganglionic sympathetic neurons and chromafn cells emigrate from the neural crest (NC). Along the craniocaudal axis, the NC can be subdivided into dif- ferent areas: cranial,