SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma
SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma
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DOI：
10.1530/erc-18-0538
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发表时间：
2019-03-01
影响因子：
3.9
通讯作者：
Martinez-Barbera, J. P.
中科院分区：
文献类型：
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作者：
Carreno, G.;Boult, J. K. R.;Martinez-Barbera, J. P.
药物抑制sonic hedgehog(SHH)途径对某些癌症有益，但对其他癌症有害。成釉细胞性颅咽管瘤(ACP)是一种相关的垂体瘤，累及儿童和成人，长期随访时发病率高，死亡率高。我们先前已经证明SHH通路在人和小鼠ACP中都被过度激活。在这里，我们表明，这种激活是配体依赖的，并由SHH蛋白在一小部分肿瘤细胞中的表达诱导。我们利用ACP小鼠模型，通过磁共振成像(MRI)引导的临床前研究，研究了SHH信号在ACP中的功能相关性。使用临床批准的SHH途径抑制剂vismodegib治疗，由于高度增殖和血管化的未分化肿瘤的过早发展，导致中位存活率显著降低。增强了小鼠的数据，SHH通路在人ACP中的抑制导致了肿瘤细胞在体外、外植体培养和体内患者来源的异种移植模型中的显著增加。综上所述，我们的结果证实了vismodegib介导的SHH通路抑制ACP的促癌作用。
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.