期刊
ENDOCRINE-RELATED CANCER
卷 26, 期 3, 页码 355-366出版社
BIOSCIENTIFICA LTD
DOI: 10.1530/ERC-18-0538
关键词
craniopharyngioma; pituitary; SHH; vismodegib; tumour
资金
- Cancer Research UK
- Children's Cancer and Leukaemia Group
- Children with Cancer UK [15/190]
- MRC [MR/M125/1]
- Brain Tumour Charity (SIGNAL)
- Brain Tumour Charity (EVEREST)
- Great Ormond Street Hospital Children's Charity
- Morgan Adams Foundation
- National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London
- CR-UK
- Department of Health (England) [C1060/A16464]
- Wellcome Trust
- MRC [MR/M000125/1] Funding Source: UKRI
Pharmacological inhibition of the sonic hedgehog (SHH) pathway can be beneficial against certain cancers but detrimental in others. Adamantinomatous craniopharyngioma (ACP) is a relevant pituitary tumour, affecting children and adults, that is associated with high morbidity and increased mortality in long-term follow up. We have previously demonstrated overactivation of the SHH pathway in both human and mouse ACP. Here, we show that this activation is ligand dependent and induced by the expression of SHH protein in a small proportion of tumour cells. We investigate the functional relevance of SHH signalling in ACP through magnetic resonance imaging (MRI)-guided preclinical studies using an ACP mouse model. Treatment with vismodegib, a clinically approved SHH pathway inhibitor, results in a significant reduction in median survival due to premature development of highly proliferative and vascularised undifferentiated tumours. Reinforcing the mouse data, SHH pathway inhibition in human ACP leads to a significant increase in tumour cell proliferation both ex vivo, in explant cultures, and in vivo, in a patient-derived xenograft model. Together, our results demonstrate a protumourigenic effect of vismodegib-mediated SHH pathway inhibition in ACP.
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