Novel paracrine modulation of Notch-DLL4 signaling by fibulin-3 promotes angiogenesis in high-grade gliomas.
Novel paracrine modulation of Notch-DLL4 signaling by fibulin-3 promotes angiogenesis in high-grade gliomas.
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DOI：
10.1158/0008-5472.can-14-0685
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Viapiano MS
中科院分区：
文献类型：
--
作者：
Nandhu MS;Hu B;Cole SE;Erdreich-Epstein A;Rodriguez-Gil DJ;Viapiano MS
高级别胶质瘤的特点是血管生成旺盛，弥漫性浸润和显著的化疗耐药性，导致复发表型，使其不可能在长期内根除。靶向胶质瘤微环境中的促肿瘤信号可能对肿瘤细胞和促进其生长的支持生态位产生重大影响。Fibulin-3是一种由神经胶质瘤细胞分泌的蛋白质，但在正常大脑中不存在，它促进肿瘤侵袭和存活。我们在这里表明，fibulin-3是一种旁分泌激活剂的Notch信号在内皮细胞和促进胶质瘤血管生成。在胶质瘤异种移植模型中，Fibulin-3过表达增加了肿瘤VEGF水平、微血管密度和血管通透性，而Fibulin-3敲低降低了血管密度。Fibulin-3在人胶质母细胞瘤中的定位显示肿瘤血管周围有致密的纤维样凝聚物，这在正常脑中是不存在的，这表明该蛋白与肿瘤内皮有显著的关联。在细胞水平，fibulin-3增强了内皮细胞的运动性和与胶质瘤细胞的结合，减少了内皮细胞发芽，并增加了内皮小管的形成，以VEGF非依赖性和Notch依赖性的方式。Fibulin-3通过抑制金属蛋白酶抑制剂TIMP 3增加内皮细胞中的ADAM 10/17活性;这导致Notch切割增加和DLL 4表达增加，与VEGF信号传导无关。抑制ADAM 10/17或敲低DLL 4降低了培养物中fibulin-3的促血管生成作用。总之，这些结果揭示了一种新的，促血管生成的作用，fibulin-3在胶质瘤，突出了这种蛋白质作为一个重要的分子靶点在肿瘤微环境的相关性。
High-grade gliomas are characterized by exuberant vascularization, diffuse invasion and significant chemoresistance, resulting in a recurrent phenotype that makes them impossible to eradicate in the long-term. Targeting pro-tumoral signals in the glioma microenvironment could have significant impact against tumor cells and the supporting niche that facilitates their growth. Fibulin-3 is a protein secreted by glioma cells, but absent in normal brain, that promotes tumor invasion and survival. We show here that fibulin-3 is a paracrine activator of Notch signaling in endothelial cells and promotes glioma angiogenesis. Fibulin-3 overexpression increased tumor VEGF levels, microvascular density, and vessel permeability, while fibulin-3 knockdown reduced vessel density in xenograft models of glioma. Fibulin-3 localization in human glioblastomas showed dense fiber-like condensations around tumor blood vessels, which were absent in normal brain, suggesting a remarkable association of this protein with tumor endothelium. At the cellular level, fibulin-3 enhanced endothelial cell motility and association to glioma cells, reduced endothelial cell sprouting, and increased formation of endothelial tubules, in a VEGF-independent and Notch-dependent manner. Fibulin-3 increased ADAM10/17 activity in endothelial cells by inhibiting the metalloprotease inhibitor TIMP3; this resulted in increased Notch cleavage and increased expression of DLL4 independently of VEGF signaling. Inhibition of ADAM10/17 or knockdown of DLL4 reduced the pro-angiogenic effects of fibulin-3 in culture. Taken together, these results reveal a novel, pro-angiogenic role of fibulin-3 in gliomas, highlighting the relevance of this protein as an important molecular target in the tumor microenvironment.