The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis
The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis
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DOI：
10.1093/cvr/cvw166
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发表时间：
2016-09-01
影响因子：
10.8
通讯作者：
Shindo, Takayuki
中科院分区：
文献类型：
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作者：
Tanaka, Megumu;Koyama, Teruhide;Shindo, Takayuki
AIMS控制血管完整性有望成为癌症和心血管疾病的新治疗靶点。肾上腺髓质素(AM)及其受体调节蛋白RAMP2被认为是心血管内环境平衡的重要调节因子。在这项研究中，我们使用可诱导的血管内皮细胞特异性RAMP2基因敲除(DI-ERAMP22/2)小鼠来阐明内源性AM-RAMP2系统在血管生成和转移中的作用。方法和结果在DI-E-RAMP2(-/-)小鼠皮下移植的肉瘤或黑色素瘤细胞生长和血管生成均低于对照组。另一方面，将B16BL6黑色素瘤细胞移植到后肢足垫后，DI-E-RAMP2(-/-)小鼠的肺自发转移增加。RAMP2基因缺失后早期，DI-E-RAMP2(-/-)小鼠出现血管通透性增强、内皮细胞-间充质转化(EndMT)样改变和全身性水肿。在DI-E-RAMP2(-/-)小鼠肺内，肺内皮细胞变形，炎症细胞渗入血管壁，表达趋化因子S100A8/9和SAA3，趋化因子S100A8/9和SAA3吸引肿瘤细胞，介导转移前生态位的形成。相反，RAMP2的过表达抑制了肿瘤细胞与内皮细胞的黏附，肿瘤转移，并提高了生存率。结论这些发现表明AM-RAMP2系统调节血管的完整性，而RAMP2的缺失通过破坏血管结构的稳定性和诱导炎症，促进原发灶内的血管通透性和EndMT样改变，并在远处器官形成转移前的生态位。因此，AM-RAMP2系统调节的血管完整性有望成为抑制肿瘤转移的治疗靶点。
Aims Controlling vascular integrity is expected to be a novel therapeutic target of cancers as well as cardiovascular diseases. Adrenomedullin (AM) and its receptor-modulating protein, RAMP2, have been identified as essential mediators of cardiovascular homeostasis. In this study, we used inducible vascular endothelial cell-specific RAMP2 knockout (DI-ERAMP22/2) mice to clarify the contribution made by the endogenous AM-RAMP2 system to angiogenesis and metastasis.Methods and resultsaEuro integral Subcutaneously transplanted sarcoma or melanoma cells showed less growth and angiogenesis in DI-E-RAMP2(-/-) than in control mice. On the other hand, after the transplantation of B16BL6 melanoma cells into hindlimb footpads, spontaneous metastasis to the lung was enhanced in DI-E-RAMP2(-/-) mice. Early after RAMP2 gene deletion, DI-E-RAMP2(-/-) mice showed enhanced vascular permeability, endothelial-mesenchymal transition (EndMT)-like change, and systemic oedema. Within the lungs of DI-E-RAMP2(-/-) mice, pulmonary endothelial cells were deformed, and inflammatory cells infiltrated the vessel walls and expressed the chemotactic factors S100A8/9 and SAA3, which attract tumour cells and mediate the formation of a pre-metastatic niche. Conversely, the overexpression of RAMP2 suppressed tumour cell adhesion to endothelial cells, tumour metastasis, and improved survival.ConclusionaEuro integral These findings indicate that the AM-RAMP2 system regulates vascular integrity, whereas RAMP2 deletion promotes vascular permeability and EndMT-like change within primary lesions and formation of pre-metastatic niches in distant organs by destabilizing the vascular structure and inducing inflammation. Vascular integrity regulated by the AM-RAMP2 system could thus be a hopeful therapeutic target for suppressing tumour metastasis.