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首页> 美国卫生研究院文献>Neuro-Oncology >AI-23PERIOSTIN REGULATES TUMOR RESISTANCE TO ANTIANGIOGENIC THERAPY THROUGH EMT AND ANGIOGENESIS-RELATED MECHANISMS IN GLIOMA STEM CELL MODELS
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AI-23PERIOSTIN REGULATES TUMOR RESISTANCE TO ANTIANGIOGENIC THERAPY THROUGH EMT AND ANGIOGENESIS-RELATED MECHANISMS IN GLIOMA STEM CELL MODELS

机译：AI-23骨膜素通过胶质瘤干细胞模型中的EMT和与血管生成相关的机制来调节抗肿瘤治疗的抗药性。

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Periostin (osteoblast-specific factor 2, POSTN) is able to interact with multiple integrins to coordinate a variety of cellular processes, including cell proliferation, EMT (epithelial-mesenchymal transition) and cell migration. Recent studies revealed that periostin plays an important role in tumor development and is up-regulated in a wide variety of tumors. In the present study, we investigated the role of periostin and its receptor in tumor invasion and resistance to antiangiogenic therapy in a panel of glioma stem cell lines. The expression status of periostin was analyzed by western blot. Periostin expression in vitro was elevated in multiple GSCs including several lines of the mesenchymal subclass. All GSCs expressed the periostin receptor integrin-beta1 but only 2 of 10 lines (20%) expressed the integrin-beta3 receptor (GSC11 and GSC17). Stable knockdown of periostin expression using specific shRNA abrogated expression of multiple EMT (CAMK2N1, COL1A2, KRT14, COL3A1 and MMP-9) and angiogenesis-related (ANGPTL4, VEGFA, CXCL5, HPSE and EFNA3) genes compared to controls. Consistent with these results, expression of HIF-1 alpha and phosphorylation of STAT3 were decreased following knockdown of periostin. However, cell cycle related genes (CyclinD1 and CyclinD2) were unaffected. Moreover, recombinant periostin increased VEGF expression and glioma cell invasion in vitro. We demonstrated in previous studies that bevacizumab (Avastin, Roche/Genentech) increased glioblastoma invasion in vivo and acquired resistance to bevacizumab was associated with an increase in periostin levels in vivo. Bevacizumab and periostin shRNA-treated animals were evaluated for expression of the stem cell marker nestin. The number of nestin-positive cells decreased in shRNA-periostin NSC11 tumors alone and following bevacizumab treatment compared to controls. Detailed mechanisms of periostin-related resistance are being elucidated. Collectively, our data suggests that periostin appears to play an important role in glioma invasion, resistance to antiangiogenic therapy and may regulate mesenchymal differentiation.
机译：骨膜素（成骨细胞特异性因子2，POSTN）能够与多种整合素相互作用，以协调多种细胞过程，包括细胞增殖，EMT（上皮-间质转化）和细胞迁移。最近的研究表明，骨膜素在肿瘤的发展中起着重要的作用，并且在多种肿瘤中上调。在本研究中，我们调查了骨膜干细胞系中骨膜素及其受体在肿瘤侵袭和抗血管生成治疗抗性中的作用。通过蛋白质印迹分析骨膜蛋白的表达状态。在包括多个间充质亚类的多个GSC中，骨膜素的体外表达均升高。所有GSC均表达骨膜素受体整联蛋白-beta1，但10个品系中只有2个（20％）表达整联蛋白-beta3受体（GSC11和GSC17）。与对照相比，使用特异性shRNA稳定地降低了骨膜蛋白的表达，消除了多个EMT（CAMK2N1，COL1A2，KRT14，COL3A1和MMP-9）和与血管生成相关的基因（ANGPTL4，VEGFA，CXCL5，HPSE和EFNA3）的表达。与这些结果一致，在敲除骨膜素后，HIF-1α的表达和STAT3的磷酸化降低。但是，细胞周期相关基因（CyclinD1和CyclinD2）不受影响。而且，重组骨膜素在体外增加了VEGF的表达和神经胶质瘤细胞的侵袭。我们在先前的研究中证明贝伐单抗（Avastin，Roche / Genentech）增加了体内胶质母细胞瘤的侵袭，并且获得的对贝伐单抗的耐药性与体内骨膜素水平的升高有关。评价贝伐单抗和骨膜素shRNA处理的动物的干细胞标志物巢蛋白的表达。与对照组相比，在单独的shRNA-骨膜素NSC11肿瘤中以及在贝伐单抗治疗后，巢蛋白阳性细胞数量减少。人们正在阐明与骨膜素相关的抗药性的详细机制。总体而言，我们的数据表明，骨膜素似乎在神经胶质瘤的侵袭，抗血管生成治疗的耐药性中可能起重要作用，并可能调节间充质分化。

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