Reelin signalling in neuroblastoma: Migratory switch in metastatic stages

Abstract

The essential functions of Reelin for the migratory behaviour of neuroblasts in the central nervous system are well documented. Its role in the dissemination of neuronal tumours of the peripheral nervous system has not been studied in detail. Here, we examined neuroblastoma (NB), a tumour derived from sympathoadrenal cells of neural crest origin. We studied the expression of Reelin, its receptors VLDLR and LRP8 and the adapter protein DAB1 in primary tumour samples and cell lines. We used real-time RT-PCR, immunohistology and western blot analysis. In NB cell lines we studied effects of all-trans retinoic acid and the in vitro effects of Reelin. In primary tumour samples of untreated patients, a significant downregulation of Reelin and DAB1 mRNA was found in the metastatic stages 3, 4 and 4s. Immunohistochemical studies revealed expression of Reelin, LRP8 and DAB1 in differentiating-type low-grade NB. In vitro, western blot analysis of selected NB cell lines showed variable expression patterns. Differentiation induction with all-trans retinoic acid induced the upregulation of Reelin and DAB1. Reelin acted as a chemoattractant for various NB cell lines but inhibited migration when applied together with the NB cells. In normal tissue, we found Reelin in lymphatic endothelial cells (LECs) but not in blood vessel endothelium (BECs). In primary NB, both BECs and LECs were positive. Our data strongly suggest that Reelin has a dual role in NB. Autocrine expression marks low-grade differentiating tumour cells, whereas paracrine Reelin presented by LECs and BECs may act as a chemoattractant and promote hematogenic and lymphogenic dissemination in progressed stages.

ApoER2 processing by presenilin‐1 modulates reelin expression

“…Evidence also suggests a role for reelin in autocrine signaling. A dual role for reelin in both autocrine and paracrine signaling has recently been suggested in neuroblastomas (54). Glutamatergic cerebellar granule neurons, which synthesize reelin, have been shown also to coexpress ApoER2 (55).…”

Disabled‐1 is down‐regulated in clinical breast cancer and regulates cell apoptosis through NF‐κB/Bcl‐2/caspase‐9

“…Dab1 has been reported to be strongly down‐regulated in glioblastoma and neuroblastoma . In breast cancer, McAvoy has firstly reported the down‐regulation of Dab1, and overexpression of Dab1 resulted in decreased cell survival .…”

“…Bcl2 family was reported to be crucial in regulating the intrinsic apoptosis pathway, 13 and we found decreased Dab1 has been reported to be strongly down-regulated in glioblastoma 17 and neuroblastoma. 18 In breast cancer, McAvoy has firstly reported the down-regulation of Dab1, and overexpression of Dab1 resulted in decreased cell survival. 6 Here, according to our study, the inhibited cell survival caused by Dab1 was resulted from…”

Endothelial and Accessory Cell Interactions in Neuroblastoma Tumor Microenvironment

“…However, reelin expression is not limited to the normal tissues such as brain, but is also detected in several different tumor pathologies where it has been linked with tumor aggressiveness [144]. A recent study suggests that reelin signaling regulates a migratory switch promoting metastasis in NB [145]. Reelin expression is negatively regulated by miR-128, a brain-enriched microRNA.…”

“…It is also expressed in blood vessels in several NB cell lines, but not in normal tissue. Therefore, it is postulated that in addition to the autocrine function, paracrine reelin presented by NB blood vessels may act as a chemoattractant and promote hematogenic and lymphogenic dissemination in NB progression [145].…”