Cancer Res:纤蛋白-3激活Notch通路促进神经胶质细胞瘤恶性

6月4日Cancer Research杂志在线报道了纤蛋白-3促进肿瘤侵袭的机制研究新发现。纤蛋白-3是一种不存在于正常大脑，而在神经胶质细胞瘤中显著上调的基质蛋白。其促进肿瘤侵袭的机制不明。恶性神经胶质细胞瘤是高侵袭性、化疗抵抗性脑瘤，预后极差。浸润性神经胶质细胞瘤细胞是复发的主要来源。针对触发侵袭和化疗抵抗的可溶性因子，也许可以对这类癌细胞有显著的抑制效果。

这项研究揭示：纤蛋白-3作为Notch信号通路的一种新的可溶性激活蛋白，对抗Notch的自分泌抑制物DDL3，并以不依赖于Notch的方式促进肿瘤细胞的生存和侵袭。运用可诱导下调策略，研究者发现纤蛋白-3的可控性下调降低了Notch通路活性，进而导致细胞凋亡增加，胶质母细胞瘤启动细胞的自我更新性下降，以及颅内癌细胞生长和扩散的抑制。此外，纤蛋白-3表达还与Notch依赖的基因表达水平相关，而且是患者来源神经胶质细胞瘤标本中Notch通路激活的标志。

这些发现再次证明，肿瘤细胞外基质通过激活Notch通路，调节神经胶质细胞瘤侵袭和对抗凋亡中发挥重要作用。尤为重要的是，研究者在肿瘤模型中，发现了一种非经典的Notch通路可溶性激活因子。他们还阐明了，在肿瘤微环境中Notch通路是如何肿瘤特异性因子所下调的。（生物谷bioon.com)

doi:10.1016/j.cell.2011.10.017
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Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling

Bin Hu1, Mohan S Nandhu1, Hosung Sim1, Paula A Agudelo-Garcia1, Joshua C Saldivar1, Claire E Dolan1, Maria E Mora1, Gerard J. Nuovo2, Susan E Cole3, and Mariano S Viapiano1,*

Malignant gliomas are highly invasive and chemoresistant brain tumors with extremely poor prognosis. Targeting of the soluble factors that trigger invasion and resistance therefore could have a significant impact against the infiltrative glioma cells that are a major source of recurrence. Fibulin-3 is a matrix protein that is absent in normal brain but upregulated in gliomas and promotes tumor invasion by unknown mechanisms. Here, we show that fibulin-3 is a novel soluble activator of Notch signaling that antagonizes DLL3, an autocrine inhibitor of Notch, and promotes tumor cell survival and invasion in a Notch-dependent manner. Using a strategy for inducible knockdown, we found that controlled downregulation of fibulin-3 reduced Notch signaling and led to increased apoptosis, reduced self-renewal of glioblastoma initiating cells, and impaired growth and dispersion of intracranial tumors. In addition, fibulin-3 expression correlated with expression levels of Notch-dependent genes and was a marker of Notch activation in patient-derived glioma samples. These findings underscore a major role for the tumor extracellular matrix in regulating glioma invasion and resistance to apoptosis via activation of the key Notch pathway. More importantly, this work describes a non-canonical, soluble activator of Notch in a cancer model and demonstrates how Notch signaling can be reduced by targeting tumor-specific accessible molecules in the tumor microenvironment.