Paradoxical role of β8 integrin on angiogenesis and vasculogenic mimicry in glioblastoma.
Paradoxical role of β8 integrin on angiogenesis and vasculogenic mimicry in glioblastoma.
复制标题
DOI：
10.1038/s41419-022-04959-7
复制
发表时间：
2022-06-08
影响因子：
9
通讯作者：
Ke, Yiquan
中科院分区：
文献类型：
--
作者：
Liu, Yang;Xu, Xiangdong;Zhang, Yuxuan;Mo, Yunzhao;Sun, Xinlin;Shu, Lingling;Ke, Yiquan
多形性胶质母细胞瘤（GBM）是最具侵袭性和高度血管化的脑肿瘤，预后差。内皮细胞依赖性血管生成和肿瘤细胞依赖性血管生成拟态（VM）协同促进胶质瘤血管化和进展。然而，GBM血管化的机制仍不清楚。在这项研究中，GBM干细胞（GSC）分为高和低β8整合素（ITGB 8）亚群。进行共培养测定，随后进行细胞计数试剂盒-8（CCK-8）、迁移、基质胶管形成和发芽测定，以评估GBM细胞和人脑微血管内皮细胞（hBMEC）的增殖、迁移和血管生成能力。构建颅内胶质瘤模型以评估ITGB 8对体内肿瘤血管化的作用。我们的研究结果表明，ITGB 8在GSC中的表达升高，并与胶质瘤组织中的干细胞标志物呈正相关，并且可以通过缺氧和p38激活来诱导。GSCs中的ITGB 8抑制hBMEC的血管生成，同时促进其网络形成能力和VM相关蛋白的表达。原位GBM模型显示ITGB 8有助于减少血管生成，同时增强侵袭性和VM形成。机制研究表明，ITGB 8-TGFβ1轴通过Smad 2/3-RhoA信号通路调控VM和上皮-间质转化（EMT）过程。总之，我们的研究结果证明了ITGB 8在GBM中调节血管生成和VM形成中的不同作用，并表明ITGB 8的药理学抑制可能代表了治疗GBM的有希望的治疗策略。
Glioblastoma multiforme (GBM) is the most aggressive and highly vascularized brain tumor with poor prognosis. Endothelial cell-dependent angiogenesis and tumor cell-dependent Vasculogenic mimicry (VM) synergistically contribute to glioma vascularization and progression. However, the mechanism underlying GBM vascularization remains unclear. In this study, GBM stem cells (GSCs) were divided into high and low β8 integrin (ITGB8) subpopulations. Co-culture assays followed by Cell Counting Kit-8 (CCK-8), migration, Matrigel tube formation, and sprouting assays were conducted to assess the proliferative, migratory and angiogenic capacity of GBM cells and human brain microvascular endothelial cells (hBMECs). An intracranial glioma model was constructed to assess the effect of ITGB8 on tumor vascularization in vivo. Our results indicated that ITGB8 expression was elevated in GSCs and positively associated with stem cell markers in glioma tissues, and could be induced by hypoxia and p38 activation. ITGB8 in GSCs inhibited the angiogenesis of hBMECs in vitro, while it promoted the ability of network formation and expression of VM-related proteins. The orthotopic GBM model showed that ITGB8 contributed to decreased angiogenesis, meanwhile enhanced invasiveness and VM formation. Mechanistic studies indicated that ITGB8-TGFβ1 axis modulates VM and epithelial-mesenchymal transition (EMT) process via Smad2/3-RhoA signaling. Together, our findings demonstrated a differential role for ITGB8 in the regulation of angiogenesis and VM formation in GBM, and suggest that pharmacological inhibition of ITGB8 may represent a promising therapeutic strategy for treatment of GBM.
登录
查看更多内容
DOI：
10.1242/dev.113746
发表时间：
2015-12-15
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Hirota S;Clements TP;Tang LK;Morales JE;Lee HS;Oh SP;Rivera GM;Wagner DS;McCarty JH
通讯作者：
McCarty JH
影响因子：
8
作者：
Guerrero PA;Tchaicha JH;Chen Z;Morales JE;McCarty N;Wang Q;Sulman EP;Fuller G;Lang FF;Rao G;McCarty JH
通讯作者：
McCarty JH
影响因子：
5.2
作者：
Jin, Sha;Lee, Wei-Chun;Cordes, Nils
通讯作者：
Cordes, Nils
DOI：
10.1523/jneurosci.5648-11.2012
发表时间：
2012-01-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Arnold TD;Ferrero GM;Qiu H;Phan IT;Akhurst RJ;Huang EJ;Reichardt LF
通讯作者：
Reichardt LF
DOI：
10.1016/j.ymthe.2021.08.011
发表时间：
2022-02-02
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Lin X;Zhuang S;Chen X;Du J;Zhong L;Ding J;Wang L;Yi J;Hu G;Tang G;Luo X;Liu W;Ye F
通讯作者：
Ye F