Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization
Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization
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DOI：
10.1172/jci70683
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发表时间：
2014-10-01
影响因子：
15.9
通讯作者：
Cavallaro, Ugo
中科院分区：
文献类型：
--
作者：
Magrini, Elena;Villa, Alessandra;Cavallaro, Ugo
虽然肿瘤血管与正常血管系统共享许多特征，但它们也表现出形态和功能异常。例如，介导神经突生长、成束和寻路的神经粘附分子L1在肿瘤脉管系统上表达。在这里，使用原位小鼠胰腺癌模型，我们评估了L1在癌血管中的功能。在内皮细胞中特异性缺乏L1或用抗L1抗体治疗的荷瘤小鼠表现出血管生成减少和血管稳定性改善，导致肿瘤生长和转移减少。与L1对肿瘤血管系统的这些显著作用一致，L1在培养的内皮细胞（EC）中的异位表达促进了表型和功能改变，包括增殖、迁移、小管形成、增强的血管通透性和内皮向间充质转化。L1诱导EC转录组的全局变化，改变了内皮病理生理学基础的几个调控网络，包括JAK/STAT介导的通路。特别地，L1诱导IL-6介导的STAT 3磷酸化，并且抑制IL-6/JAK/STAT信号传导轴阻止L1诱导的EC增殖和迁移。对患者样本的评估显示，与非癌组织相比，L1表达在人胰腺癌血管和其他肿瘤类型血管中特异性增强。总之，这些数据表明，内皮L1协调多种癌血管功能，并代表了肿瘤血管特异性治疗的潜在靶点。
While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we evaluated L1 functionality in cancer vessels. Tumor-bearing mice specifically lacking L1 in endothelial cells or treated with anti-L1 antibodies exhibited decreased angiogenesis and improved vascular stabilization, leading to reduced tumor growth and metastasis. In line with these dramatic effects of L1 on tumor vasculature, the ectopic expression of L1 in cultured endothelial cells (ECs) promoted phenotypical and functional alterations, including proliferation, migration, tubulogenesis, enhanced vascular permeability, and endothelial-to-mesenchymal transition. L1 induced global changes in the EC transcriptome, altering several regulatory networks that underlie endothelial pathophysiology, including JAK/STAT-mediated pathways. In particular, L1 induced IL-6-mediated STAT3 phosphorylation, and inhibition of the IL-6/JAK/STAT signaling axis prevented L1-induced EC proliferation and migration. Evaluation of patient samples revealed that, compared with that in noncancerous tissue, L1 expression is specifically enhanced in blood vessels of human pancreatic carcinomas and in vessels of other tumor types. Together, these data indicate that endothelial L1 orchestrates multiple cancer vessel functions and represents a potential target for tumor vascular-specific therapies.