The essential role of fibroblasts in esophageal squamous cell carcinoma-induced angiogenesis
The essential role of fibroblasts in esophageal squamous cell carcinoma-induced angiogenesis
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DOI：
10.1053/j.gastro.2008.02.061
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发表时间：
2008-06-01
期刊：
影响因子：
29.4
通讯作者：
Herlyn, Meenhard
中科院分区：
文献类型：
--
作者：
Noma, Kazuhiro;Smalley, Keiran S. M.;Herlyn, Meenhard
背景与目的：食管鳞状细胞癌（ESCC）是一种高度血管生成的肿瘤。在这里，我们研究的作用，基质成纤维细胞在食管鳞癌诱导的血管生成反应，使用一种新的三维模型。方法：建立一种新的方法，将食管鳞癌和食管癌细胞共培养。成纤维细胞诱导人微血管内皮细胞（HMVEC）血管网络形成的三维胶原凝胶。生物化学研究表明，ESCC诱导的成纤维细胞活化是通过转化生长因子（TGF）-β和血管内皮生长因子（VEGF）依赖性途径诱导血管网络形成所必需的。结果：来自一组4个ESCC系的条件培养基通过TGF-β信号转导将正常食管成纤维细胞转分化为肌成纤维细胞。成纤维细胞的存在对于有效的HMVEC网络形成是必不可少的，并且向这些培养物中加入ESCC细胞大大增强了血管生成过程。TGF-β抑制剂处理后，网络形成完全受到抑制，表明TGF-β在此过程中的作用。最后，我们发现，ESCC衍生的TGF-β通过从成纤维细胞释放VEGF来调节血管生成，并且VEGF释放在TGF-β抑制后被阻断。结论：这项研究显示了成纤维细胞在ESCC血管生成诱导反应中的重要作用，并表明TGF-β信号轴的药理学靶向可能对这种致命疾病具有治疗益处。
Background & Aims: Esophageal squamous cell carcinoma (ESCC) is known to be a highly angiogenic tumor. Here, we investigated the role of the stromal fibroblasts in the ESCC-induced angiogenic response using a novel 3-dimensional model. Methods: A novel assay was developed where cocultures of ESCC and esophageal. fibroblasts induced human microvascular endothelial cell (HMVEC) vascular network formation in a 3-dimensional collagen gel. Biochemical studies showed that the ESCC-induced activation of the fibroblasts was required to induce vascular network formation via a transforming growth factor (TGF)-beta and vascular endothelial growth factor (VEGF)-dependent pathway. Results: Conditioned media from a panel of 4 ESCC lines transdifferentiated normal esophageal fibroblasts into myofibroblasts via TGF-beta signaling. The presence of fibroblasts was essential for efficient HMVEC network formation, and the addition of ESCC cells to these cultures greatly enhanced the angiogenic process. The role of TGF-beta in this process was shown by the complete inhibition of network formation following TGF-beta inhibitor treatment. Finally, we showed that ESCC-derived TGF-beta regulates angiogenesis through the release of VEGF from the fibroblasts and that the VEGF release was blocked following TGF-beta inhibition. Conclusions: This study shows the essential role of fibroblasts in the ESCC angiogenic-induced response and suggests that the pharmacologic targeting of the TGF-beta signaling axis could be of therapeutic benefit in this deadly disease.