根據(jù)來(lái)自美國(guó)俄亥俄州立大學(xué)綜合癌癥中心–Arthur G. James腫瘤醫(yī)院和Richard J. Solove研究所(The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute)的研究人員開展的一項(xiàng)研究,，感染著腫瘤殺手病毒(tumor-killing virus)的腦瘤細(xì)胞釋放一種起著“警鈴(alarm bell)”作用的蛋白來(lái)通知其他的腫瘤細(xì)胞即將來(lái)臨的病毒感染,，并能夠讓它們發(fā)動(dòng)對(duì)病毒的抵抗,。相關(guān)研究結(jié)果于2012年3月15日發(fā)表在Cancer Research期刊上。
這些被感染的腫瘤細(xì)胞將一種被稱作CCN1(Cysteine rich 61, 譯者注：也稱作CYR61)的蛋白釋放進(jìn)細(xì)胞之間的狹窄空間中,，而且在那里這種蛋白啟動(dòng)抗病毒反應(yīng)。這種反應(yīng)限制溶瘤病毒(oncolytic virus)在腫瘤內(nèi)傳播的速度,，降低它殺死癌細(xì)胞的能力,，從而限制利用這種病毒進(jìn)行抗腫瘤治療的效果。
這項(xiàng)研究提示著腫瘤細(xì)胞一般來(lái)說(shuō)可能能夠利用這種機(jī)制來(lái)有助于控制病毒復(fù)制,，同時(shí)也提示著阻斷這一反應(yīng)很可能改善治療神經(jīng)膠質(zhì)瘤(glioblastoma)的溶瘤病毒療法,，并可能改善未來(lái)的基因療法。
溶瘤病毒在腫瘤細(xì)胞中復(fù)制并殺死它們,。已有實(shí)驗(yàn)表明這種病毒有望用于治療神經(jīng)膠質(zhì)瘤---腦癌中最為常見和最為致命性的形式,。患有神經(jīng)膠質(zhì)瘤的病人在確診之后平均只能存活大約15個(gè)月,，所以人們急需要一種新的療法,。
“我們發(fā)現(xiàn)在胞外基質(zhì),，這種蛋白精心安排一種顯著性的細(xì)胞抗病毒反應(yīng)來(lái)降低病毒復(fù)制并限制它的溶細(xì)胞效應(yīng)”，主要研究員Balveen Kaur副教授說(shuō),。
“這些發(fā)現(xiàn)是比較有意義的,，因?yàn)樗鼈兘沂境霰徊《靖腥镜哪[瘤細(xì)胞利用一種新機(jī)制來(lái)對(duì)抗病毒感染，并發(fā)出警報(bào)通知周圍未被感染的腫瘤細(xì)胞做好防御以便擊退即將到來(lái)的病毒攻擊”,，Kaur說(shuō),。
Kaur注意到，CCN1有助于調(diào)節(jié)包括附著,、遷移和增殖在內(nèi)的細(xì)胞功能,，而且在68%的神經(jīng)膠質(zhì)瘤樣品中它是過(guò)表達(dá)的。
Kaur在以前的研究中就已發(fā)現(xiàn)溶瘤病毒療法誘導(dǎo)腫瘤細(xì)胞釋放CCN1到腫瘤微環(huán)境中,。在這項(xiàng)研究中,，Kaur和她的同事們使用神經(jīng)膠質(zhì)瘤細(xì)胞系、來(lái)自人皰疹病毒I型(human herpesvirus type 1, HSV-1)的溶瘤病毒和神經(jīng)膠質(zhì)瘤模式動(dòng)物來(lái)開展研究,。主要研究結(jié)果包括：
1)溶瘤病毒上調(diào)CCN1表達(dá),，但是化療或放射治療不能如此。因此,，它可能是神經(jīng)膠質(zhì)瘤細(xì)胞對(duì)病毒感染產(chǎn)生的一般對(duì)策,。
2)在胞外空間，CCN1降低病毒復(fù)制從而阻止它殺死神經(jīng)膠質(zhì)瘤細(xì)胞,。
3)CCN1通過(guò)一種整合素細(xì)胞表面受體(integrin cell-surface receptor)來(lái)誘導(dǎo)I型干擾素抗病毒反應(yīng),。
“總體而言，這項(xiàng)發(fā)現(xiàn)揭示胞外信號(hào)傳導(dǎo)如何能夠促進(jìn)腫瘤細(xì)胞清除病毒”,，Kaur說(shuō),，“我們?nèi)缃衲軌蚶眠@種知識(shí)來(lái)改善未來(lái)的抗病毒基因治療。” (生物谷：towersimper編譯)
doi:10.1158/0008-5472.CAN-11-2526
PMC:
PMID:
Extracellular Matrix Protein CCN1 Limits Oncolytic Efficacy in Glioma
Amy Haseley, Sean Boone, Jeffrey Wojton, Lianbo Yu, Ji Young Yoo, Jianhua Yu, Kazuhiko Kurozumi, Joseph C. Glorioso, Michael A. Caligiuri, and Balveen Kaur
Oncolytic viral therapy has been explored widely as an option for glioma treatment but its effectiveness has remained limited. Cysteine rich 61 (CCN1) is an extracellular matrix (ECM) protein elevated in cancer cells that modulates their adhesion and migration by binding cell surface receptors. In this study, we examined a hypothesized role for CCN1 in limiting the efficacy of oncolytic viral therapy for glioma, based on evidence of CCN1 induction that occurs in this setting. Strikingly, we found that exogenous CCN1 in glioma ECM orchestrated a cellular antiviral response that reduced viral replication and limited cytolytic efficacy. Gene expression profiling and real-time PCR analysis revealed a significant induction of type-I interferon responsive genes in response to CCN1 exposure. This induction was accompanied by activation of the Jak/Stat signaling pathway, consistent with induction of an innate antiviral cellular response. Both effects were mediated by the binding of CCN1 to the cell surface integrin α6β1, activating its signaling and leading to rapid secretion of interferon-α, which was essential for the innate antiviral effect. Together, our findings reveal how an integrin signaling pathway mediates activation of a type-I antiviral interferon response that can limit the efficacy of oncolytic viral therapy. Furthermore, they suggest therapeutic interventions to inhibit CCN1–integrin α6 interactions to sensitize gliomas to viral oncolysis.
