Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK.
Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
Endocr Relat Cancer. 2019 Mar;26(3):355-366. doi: 10.1530/ERC-18-0538.
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 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.
药物抑制 sonic hedgehog（SHH）信号通路对某些癌症可能有益，但对其他癌症则可能有害。颅咽管瘤（ACP）是一种相关的垂体肿瘤，影响儿童和成人，在长期随访中具有较高的发病率和死亡率。我们之前已经证明，人类和小鼠的 ACP 中均存在 SHH 通路的过度激活。在这里，我们证明这种激活是配体依赖性的，并由肿瘤细胞中一小部分 SHH 蛋白的表达诱导。我们通过使用 ACP 小鼠模型进行 MRI 引导的临床前研究来研究 SHH 信号在 ACP 中的功能相关性。用维莫德吉（vismodegib）治疗，一种临床批准的 SHH 通路抑制剂，由于高度增殖和血管化的未分化肿瘤的过早发育，导致中位生存期显著缩短。强化了小鼠数据，SHH 通路抑制在人类 ACP 中导致肿瘤细胞增殖显著增加，无论是在离体培养的体外实验中，还是在患者来源的异种移植模型中的体内实验中。总之，我们的结果表明，维莫德吉介导的 SHH 通路抑制在 ACP 中具有促肿瘤作用。
