Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.
Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.
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DOI：
10.1038/bjc.2017.116
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发表时间：
2017-05-23
影响因子：
8.8
通讯作者：
Bianco R
中科院分区：
文献类型：
--
作者：
Di Mauro C;Rosa R;D'Amato V;Ciciola P;Servetto A;Marciano R;Orsini RC;Formisano L;De Falco S;Cicatiello V;Di Bonito M;Cantile M;Collina F;Chambery A;Veneziani BM;De Placido S;Bianco R
一些证据表明，三阴性乳腺癌（TNBC）肿瘤发生中存在显著的血管生成依赖性，并且对抗血管生成剂具有潜在的敏感性。在此，研究了Hedgehog（Hh）途径在调节TNBC依赖性血管生成中的假定作用。Hh通路转录因子胶质瘤相关癌基因同源蛋白1（GLI 1）的表达和调节进行了研究，对内皮细胞室和TNBC引发的血管生成。为了评估我们的发现的翻译相关性，在TNBC异种移植小鼠中测试紫杉醇与Smo抑制剂NVP-LDE 225的组合。200例TNBC患者的组织微阵列分析显示GLI 1过表达与血管内皮生长因子受体2（VEGFR 2）表达配对。在体外，Hh途径以自分泌方式促进TNBC进展，调节癌细胞表面上的VEGF/VEGFR 2环，并以旁分泌方式协调肿瘤血管形成。这些作用被Smo药理学抑制抵消。在TNBC异种移植小鼠中，安排NVP-LDE 225而不是贝伐单抗提供了对TNBC细胞增殖和内皮细胞组织的更好的持续抑制。这项研究确定Hh途径是TNBC肿瘤血管生成的主要调节因子之一，从而表明Hh抑制是一种潜在的新抗血管生成治疗选择，可在GLI 1过表达的TNBC患者中进行临床研究。
Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice. Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation. This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.