6月4日Cancer Research雜志在線報(bào)道了纖蛋白-3促進(jìn)腫瘤侵襲的機(jī)制研究新發(fā)現(xiàn),。纖蛋白-3是一種不存在于正常大腦,，而在神經(jīng)膠質(zhì)細(xì)胞瘤中顯著上調(diào)的基質(zhì)蛋白。其促進(jìn)腫瘤侵襲的機(jī)制不明,。惡性神經(jīng)膠質(zhì)細(xì)胞瘤是高侵襲性,、化療抵抗性腦瘤，預(yù)后極差,。浸潤(rùn)性神經(jīng)膠質(zhì)細(xì)胞瘤細(xì)胞是復(fù)發(fā)的主要來(lái)源,。針對(duì)觸發(fā)侵襲和化療抵抗的可溶性因子，也許可以對(duì)這類癌細(xì)胞有顯著的抑制效果,。
這項(xiàng)研究揭示：纖蛋白-3作為Notch信號(hào)通路的一種新的可溶性激活蛋白,，對(duì)抗Notch的自分泌抑制物DDL3，并以不依賴于Notch的方式促進(jìn)腫瘤細(xì)胞的生存和侵襲,。運(yùn)用可誘導(dǎo)下調(diào)策略,，研究者發(fā)現(xiàn)纖蛋白-3的可控性下調(diào)降低了Notch通路活性，進(jìn)而導(dǎo)致細(xì)胞凋亡增加,，膠質(zhì)母細(xì)胞瘤啟動(dòng)細(xì)胞的自我更新性下降,，以及顱內(nèi)癌細(xì)胞生長(zhǎng)和擴(kuò)散的抑制。此外,，纖蛋白-3表達(dá)還與Notch依賴的基因表達(dá)水平相關(guān),，而且是患者來(lái)源神經(jīng)膠質(zhì)細(xì)胞瘤標(biāo)本中Notch通路激活的標(biāo)志。
這些發(fā)現(xiàn)再次證明,，腫瘤細(xì)胞外基質(zhì)通過(guò)激活Notch通路,，調(diào)節(jié)神經(jīng)膠質(zhì)細(xì)胞瘤侵襲和對(duì)抗凋亡中發(fā)揮重要作用,。尤為重要的是，研究者在腫瘤模型中,，發(fā)現(xiàn)了一種非經(jīng)典的Notch通路可溶性激活因子,。他們還闡明了，在腫瘤微環(huán)境中Notch通路是如何腫瘤特異性因子所下調(diào)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.
