Wnt/beta-catenin signalling in craniopharyngioma
Adamantinomatous craniopharyngioma (ACP) is an epithelial intracranial lesion arising from Rathkes pouch with a median age at diagnosis of 8 years. ACP is the third most common paediatric brain tumour, accounting for approximately 513% of brain tumours, and the commonest pituitary tumour among children. Although histologically benign, ACP often behaves aggressively with invasion of the hypothalamus and visual pathways. Consequences associated with both the tumour and its treatment (surgery and/or radiotherapy) include obesity and subsequent Type 2 diabetes mellitus (up to two thirds of patients), learning difficulties (psychological and educational problems), visual impairment, severe multiple pituitary hormone deficiencies and irreversible diabetes insipidus in up to 95% of patients. This high morbidity bears a vast burden to patients and families as well as considerable financial costs to health services. In a significant percentage of patients, complications may result in death.
Activating mutations in the gene encoding β-catenin have been identified in ACP and recently, using a novel mouse model, we have demonstrated a causative role for mutated β-catenin and the subsequent over-activated Wnt/ β-catenin pathway in ACP tumorigenesis. We have utilised this new genetic tool further understand the aetiology and pathogenesis of human ACP, as well as to test the efficacy of small-molecule inhibitors for treatment of these tumours. Our research has revealed that pituitary progenitors/stem cells are likely to play an important role in the oncogenic process by acting as signalling centres promoting cell proliferation and survival. In addition, we have identified several genes/pathways expressed in mouse and human ACP, thus providing novel biomarkers for studying genotype/phenotype correlations. Finally, we show that inhibiting some of these pathways may deliver targeted therapies for the treatment of these devastating childhood tumours.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.