VEGF as a modulator of the innate immune response in glioblastoma

Turkowski Kati; Brandenburg Susan; Mueller Annett; Kremenetskaia Irina; Bungert Alexander D.; Blank Anne; Felsenstein Matth?us; Vajkoczy Peter

摘要

Abstract > VEGF is an important factor in tumor vascularization and used as target for anti‐angiogenic treatment strategies in glioma. In this study, we demonstrate for the first time that VEGF is a modulator of the innate immune response with suppressive effects on the immunologic and pro‐angiogenic function of microglia/macrophages in a glioblastoma rodent model. High level of VEGF led to threefold enlarged tumor volumes and a pronounced remodeling of the vascular structure along with a reduced infiltration of microglia/macrophages by approximately 50%. Remaining microglia/macrophages showed an enhanced rate of apoptosis as well as significant downregulation of the VEGF‐receptor, VEGFR2, and others such as CXCR4. Consequently, we determined a substantially impaired migration of these microglia/macrophages to VEGF and SDF1α in vitro . Furthermore, we observed an increased presentation of the surface molecules MHCI and MHCII on microglia/macrophages from VEGF‐overexpressing gliomas that are essential for activation of the adaptive immune system. In contrast, the expression of pro‐inflammatory and suppressive cytokines, associated with the innate immune response, were mainly downregulated. Remarkably, the abundance of VEGF provoked less accumulation of microglia/macrophages within the perivascular niche and concomitantly reduced the release of pro‐angiogenic factors, like VEGF, suggesting a possible regulatory feedback mechanism. Thus, the quantity of VEGF in the glioma microenvironment seems to be crucial for the participation of microglia/macrophages on tumor progression and should be considered for developing novel therapeutic approaches. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><abstract xmlns =“http://www.wiley.com/namespaces/wiley”type =“main”> <title type =“main”>抽象</ title> > Vegf是肿瘤血管化和肿瘤血管化的重要因素用作胶质瘤中抗血管生成治疗策略的靶标。在这项研究中，我们首次证明VEGF是对胶质细胞瘤啮齿动物模型中微胶质细胞/巨噬细胞的免疫和血管生成功能的抑制作用的先天免疫应答的调节剂。高水平的VEGF导致三倍扩大的肿瘤体积和血管结构的发音重塑，并且降低了微胶质细胞/巨噬细胞的渗透率约为约50％。剩余的小胶质细胞/巨噬细胞显示出增强的细胞凋亡率以及VEGF受体，VEGFR2等的显着下调，例如CXCR4。因此，我们确定这些小胶质细胞/巨噬细胞对VEGF和SDF1α的迁移的大幅下降，体外。此外，我们观察到从VEGF过表达的Gliomas从VEGF过表达的胶质组织上增加了表面分子MHCI和MHCII的呈递，这对于激活自适应免疫系统至关重要。相反，主要是下调与先天免疫应答相关的促炎和抑制细胞因子的表达。值得注意的是，VEGF的丰富在血管外尼西肽内少累积较少的微胶质细胞/巨噬细胞积累，并伴随着VEGF等促血管生成因子的释放，表明可能的调节反馈机制。因此，胶质瘤微环境中的VEGF的数量似乎对小胶鸡/巨噬细胞对肿瘤进展的参与至关重要，并且应该被认为是制定新的治疗方法。 </ p> </ abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-23771/'>《Glia》</a> <b style="margin: 0 2px;">|</b><span>2018年第1期</span><b style="margin: 0 2px;">|</b><span>共14页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Turkowski Kati&option=202" target="_blank" rel="nofollow">Turkowski Kati;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Brandenburg Susan&option=202" target="_blank" rel="nofollow">Brandenburg Susan;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Mueller Annett&option=202" target="_blank" rel="nofollow">Mueller Annett;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Kremenetskaia Irina&option=202" target="_blank" rel="nofollow">Kremenetskaia Irina;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Bungert Alexander D.&option=202" target="_blank" rel="nofollow">Bungert Alexander D.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Blank Anne&option=202" target="_blank" rel="nofollow">Blank Anne;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Felsenstein Matth?us&option=202" target="_blank" rel="nofollow">Felsenstein Matth?us;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Vajkoczy Peter&option=202" target="_blank" rel="nofollow">Vajkoczy Peter;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> <p>Department of Experimental NeurosurgeryCharité – Universit?tsmedizin Berlin corporate member of Freie Universit?t Berlin Humboldt‐Universit?t zu Berlin and Berlin Institute of Health Charitéplatz 1Berlin 10117 Germany;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/200.html" title="神经病学与精神病学">神经病学与精神病学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=GBM&option=203" rel="nofollow">GBM;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=microglia/macrophages&option=203" rel="nofollow">microglia/macrophages;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=SDF1α&option=203" rel="nofollow">SDF1α;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=tumor angiogenesis&option=203" rel="nofollow">tumor angiogenesis;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=VEGFR2&option=203" rel="nofollow">VEGFR2;</a> </p> <div class="translation"> 机译：GBM;微胶质细胞/巨噬细胞;SDF1α;肿瘤血管生成;VEGFR2; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab 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href="/academic-journal-cn_journal-practical-medical-techniques_thesis/0201250633016.html">CD44与VEGF在颅内转移瘤与胶质母细胞瘤中的表达研究</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=熊正文&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 熊正文</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=范水平&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,范水平</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=冯骥良&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,冯骥良</a> <span> <a href="/journal-cn-6654/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 实用医技杂志 </a> </span> <span> . 2005</span><span>,第11B期</span> </span> </div> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/academic-journal-cn_journal-practical-medical-techniques_thesis/0201250589825.html">CD44与VEGF在颅内转移瘤与胶质母细胞瘤中的表达研究</a> <b>[J]</b> <span> <a 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