Exploiting the chick embryonic environment to reprogram neuroblastoma cells to a benign phenotype

Carter, Rachel Exploiting the chick embryonic environment to reprogram neuroblastoma cells to a benign phenotype. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

Neuroblastoma is a paediatric cancer that arises from the sympathetic ganglia and adrenal medulla. Tumours with MYCN amplification have the worst prognosis, and make up around 30% of neuroblastoma diagnoses. Neuroblastoma exhibits an unusually high propensity for spontaneous regression, which occurs most frequently in the youngest patients (under 18 months of age), perhaps because developmental cues still present prompt belated differentiation of the tumour cells. This led to the hypothesis that factors from an appropriate embryonic environment may be capable of activating the correct molecular switches to encourage the differentiation and/or apoptosis of neuroblastoma cells, reprogramming the tumour to a benign phenotype. To test this hypothesis, EGFP-labelled MYCN-amplified Kelly cells were injected into the extra-embryonic vitelline veins of embryonic day 3 (E3) and E6 chick embryos, and the responses of injected cells were analysed at E10 and E14. Kelly cells injected at E3 respond to neural crest migratory cues and integrate into neural crest-derived tissues: some neural, notably the sympathetic ganglia and enteric nervous system, although never the adrenal gland; and others non-neural, such as the meninges and tail. Cells injected at E6 do not show such targeting, integrating into various tissues such as the liver, kidney and meninges. The cells respond to their respective microenvironments, and in sympathetic ganglia some cells differentiate, show reduced cell division, and crucially such cells have undetectable MYCN expression by E10. In non-neural locations, cells form more rapidly dividing clumps and continue to express MYCN. The downregulation of MYCN is dependent on continuous and direct interaction with the sympathetic ganglion environment. Kelly cells’ morphology, behaviour and gene expression are altered by the sympathetic ganglia microenvironment. Taking these key observations, we speculate that the Kelly cells’ MYCN amplicon may likely contain the required DNA regulatory sequences to enable MYCN expression to be altered in response to the embryonic environment. If the factors responsible for MYCN repression can be elucidated, they may represent effective new therapeutic targets.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2013-06 (completed)
Uncontrolled Keywords:	Neuroblastoma, Chick embryo, MYCN
Subjects:	?? RC0254 ??
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	08 Aug 2013 10:48
Last Modified:	16 Dec 2022 04:39
DOI:	10.17638/00011733
Supervisors:	Moss, Diana Jesudason, Edwin
URI:	https://livrepository.liverpool.ac.uk/id/eprint/11733