The prognostic value of cancer stem cell markers in various cancer subtypes is a well documented research area. Our findings show that the stem cell marker Lgr5 is associated with an aggressive phenotype in neuroblastoma. Here, we discuss these findings within the context of recent studies in several cancers such as lung, colorectal and intestinal cancer, glioblastoma and ewing’s sarcoma. Neuroblastoma continues to be an elusive disease, due to its heterogeneous presentation ranging from spontaneous regression to aggressive metastatic disease and intertwined genetic variability. Currently, the most significant prognostic marker of high risk disease and poor prognosis is amplification of the MYCN oncogene, which is found in approximately 25% of cases [1]. With this in mind, there is still much to learn about the driving mechanisms of this aggressive paediatric tumour. Neuroblastoma development is thought to be the result of aberrant differentiation of the cell of origin, embryonic neural crest cells which then migrate and invade during the developmental stage[2]. Aberrant cells are those which would, under normal conditions form the mature tissues of the sympathetic ganglia and adrenal medulla. Tumours are known to develop indiscriminately along the radius of the sympathetic ganglia, although it is well established that the adrenal glands are fundamentally the most common primary site [3]

Neuroblastoma (NB) is a paediatric solid cancer with high fatality, relapses and acquired resistance to chemotherapy that requires new therapeutic approaches to improve survival. LGR5 is a receptor that potentiates WNT/signalling pathway and has been reported to promote development and survival in several adult cancers. In this study we investigated LGR5 expression in a panel of NB cell lines with acquired resistance to vincristine or doxorubicin. We show LGR5-LRP6 cooperation with enhanced expression in drug resistant NB cell lines compared to parental cells, suggesting a role for LGR5 in the emergence of drug resistance, warranting further investigation

Neuroblastoma (NB) is the most common paediatric solid cancer with high fatality, relapses and acquired resistance to drug therapy. The clinical challenge NB poses requires new therapeutic approaches to improve survival rates. The WNT signalling pathway is crucial in embryonic development but has also been reported to be dysregulated in glioblastoma, ovarian, breast and colorectal cancer. LGR5 is a receptor which potentiates the WNT/β-catenin signalling pathway, hence contributing to cancer stem cell proliferation and self-renewal. LGR5 has been reported to promote both development and survival of colorectal cancer and glioblastomas. Our previous study illustrated that LGR5 is associated with aggressiveness in NB cell lines established at different stages of treatment. Following these findings, we investigated whether LGR5 is involved in acquired drug resistance via the WNT pathway in NB cell lines. Cell lines in this study have an acquired drug resistance to vincristine (VCR) or doxorubicin (DOX). In this study, we showed LGR5-LRP6 cooperation with enhanced expression of both proteins in SHSY5YrVCR, IMR32rDOX, IMR5rVCR and IMR5rDOX NB cell lines compared to paired parental cells. We also found elevated expression of β-catenin in cell lines with acquired drug resistance is indicative of β-catenin-dependent WNT signalling. This study warrants further investigation into the role of the WNT signalling pathway in acquired drug resistance.

Purpose: Neuroblastoma is a paediatric tumour that develops from embryonal neural crest cells that give rise to the sympathetic nervous system. Aggressive high-risk disease remains a clinical challenge and despite multi-modal therapy, survival rates are poor. Most neuroblastomas initially respond well to induction chemotherapy however, 50-60% of patients with high-risk disease will relapse with aggressive disease. A major obstacle in the successful treatment of this disease is the development of acquired resistance to chemotherapeutic agents. We hypothesize that aggressive neuroblastomas acquire a more immature phenotype in addition to increased expression of genes linked to stem cell pathways. Methods: In this study we investigated the role of stem cell related genes in the development of acquired drug resistance using Q- Real Time PCR and bioinformatics analysis on three-paired vincristine sensitive and resistant cell lines. Results: The study outlines 11 differentially expressed genes with several targets involved primarily in notch signalling, and stem cell development. Conclusions: The findings implicated in this study, which include comparative analysis against patient microarray data, warrants further study on the functional effects of these genes/pathways to elucidate their role in acquired drug resistance.