Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor.
Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor.
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DOI：
10.1016/j.vph.2016.10.004
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发表时间：
2017-02
影响因子：
4
通讯作者：
Beck IM
中科院分区：
文献类型：
--
作者：
Drebert Z;MacAskill M;Doughty-Shenton D;De Bosscher K;Bracke M;Hadoke PWF;Beck IM
血管生成在癌症进展中是重要的，并且可以受到肿瘤相关肌成纤维细胞的影响。我们提出了糖皮质激素通过改变结肠癌来源的肌成纤维细胞释放促血管生成因子间接影响血管生成的假设。我们的研究表明，糖皮质激素降低前列腺素，尿激酶型纤溶酶原激活剂（uPA）和血管生成素样蛋白-2（ANGPTL 2）的水平，但增加血管生成素（ANG）从人CT5.3hTERT结肠癌来源的肌成纤维细胞上清液。从溶剂（CMS）和地塞米松（Dex）处理（CMD）肌成纤维细胞的条件培养基增加人脐静脉内皮细胞（HUVEC）的增殖，但不影响促血管生成因子的表达或管样结构的形成（由HUVEC或人主动脉EC）。在HUVEC划痕测定中，CMS诱导的伤口愈合加速被CMD处理减弱。此外，CMS诱导的小鼠离体主动脉环中的新血管生长也使用CMD钝化。后一种效应可归因于Dex驱动的分泌因子减少和CMD中存在的潜在残留Dex（使用地塞米松加标CMS对照品指示）。然而，划痕试验中的类似对照显示，CMD中因子水平的改变，而不是潜在的残留Dex，是导致伤口闭合降低的原因。总之，我们的研究结果表明，糖皮质激素间接改变内皮细胞功能在体内肿瘤的发展。
Angiogenesis is important in cancer progression and can be influenced by tumor-associated myofibroblasts. We addressed the hypothesis that glucocorticoids indirectly affect angiogenesis by altering the release of pro-angiogenic factors from colon cancer-derived myofibroblasts. Our study shows that glucocorticoids reduced prostanoids, urokinase-type plasminogen activator (uPA) and angiopoietin-like protein-2 (ANGPTL2) levels, but increased angiogenin (ANG) in supernatant from human CT5.3hTERT colon cancer-derived myofibroblasts. Conditioned medium from solvent- (CMS) and dexamethasone (Dex)-treated (CMD) myofibroblasts increased human umbilical vein endothelial cell (HUVEC) proliferation, but did not affect expression of pro-angiogenic factors or tube-like structure formation (by HUVECs or human aortic ECs). In a HUVEC scratch assay CMS-induced acceleration of wound healing was blunted by CMD treatment. Moreover, CMS-induced neovessel growth in mouse aortic rings ex vivo was also blunted using CMD. The latter effect could be ascribed to both Dex-driven reduction of secreted factors and potential residual Dex present in CMD (indicated using a dexamethasone-spiked CMS control). A similar control in the scratch assay, however, revealed that altered levels of factors in the CMD, and not potential residual Dex, were responsible for decreased wound closure. In conclusion, our results suggest that glucocorticoids indirectly alter endothelial cell function during tumor development in vivo.