我國(guó)學(xué)者對(duì)惡性腦膠質(zhì)瘤的治療研究又有新進(jìn)展。研究發(fā)現(xiàn),，將融合基因工程化的溶瘤病毒融入體外培養(yǎng)的膠質(zhì)瘤干細(xì)胞中,，不僅能夠顯著抑制膠質(zhì)瘤干細(xì)胞的活性,，降低腫瘤細(xì)胞的侵襲能力,，且能表達(dá)具有生物活性的內(nèi)皮抑素－血管生成抑素（Endo-Angio）融合蛋白，展示了良好的治療前景,。這項(xiàng)由國(guó)家自然科學(xué)基金資助,、首都醫(yī)科大學(xué)附屬北京天壇醫(yī)院神經(jīng)外科、北京市神經(jīng)外科研究所劉福生教授與加拿大哥倫比亞大學(xué)神經(jīng)外科腦研究中心William Jia教授等,，完成的相關(guān)研究論文,，近日在國(guó)際知名刊物《腦研究》（Brain Research,，2011，1390C: 59-69)雜志發(fā)表,。
腦膠質(zhì)瘤的發(fā)病率約占顱內(nèi)原發(fā)腫瘤的50%,，每年全球約有近60萬(wàn)中青年人死于該病，對(duì)于腦膠質(zhì)瘤的治療,，一直是神經(jīng)外科領(lǐng)域一道最棘手的研究課題。盡管通過(guò)手術(shù),、放療,、化療等綜合治療能延長(zhǎng)患者生命，但是多數(shù)惡性膠質(zhì)瘤患者中位生存期僅為12~18個(gè)月,，臨床迫切需要尋找新的治療方法,。
研究發(fā)現(xiàn)，膠質(zhì)瘤靶基因有多種,，而基因的表達(dá)依賴于細(xì)胞的長(zhǎng)期存活,，其中以腫瘤的血管生成作為靶點(diǎn)，通過(guò)抑制血管的形成達(dá)到基因治療是最具潛力的方法之一,。通過(guò)基因工程化的溶瘤病毒,，不僅可發(fā)揮溶瘤病毒強(qiáng)大的裂解腫瘤細(xì)胞的特性，而且能夠抑制腫瘤血管的生成,，對(duì)腦惡性腫瘤的治療具有重要的意義,。為此，劉福生等采用的基因工程化的溶瘤病毒是在天然HSV-1病毒F株基礎(chǔ)上,，將病毒基因組中ICP34.5和ICP6的雙基因敲除,，插入人Endo-Angio融合基因進(jìn)行改造，以使該病毒既具有溶解腫瘤干細(xì)胞的溶瘤性質(zhì),，又能夠使腫瘤細(xì)胞在溶解前表達(dá)Endo-Angio外源基因,，從而抑制干細(xì)胞血管巢內(nèi)的血管形成。
為了證實(shí)溶瘤病毒的獨(dú)具作用,，劉福生等從20例惡性膠質(zhì)瘤標(biāo)本中成功分離出4例具有干細(xì)胞特征的膠質(zhì)瘤干細(xì)胞,，用于研究溶瘤病毒對(duì)膠質(zhì)瘤干細(xì)胞的溶瘤作用，并觀察Endo-Angio外源基因的表達(dá)及其活性,。
結(jié)果發(fā)現(xiàn),，分離出的膠質(zhì)瘤干細(xì)胞成球狀生長(zhǎng)，CD133及Nestin表達(dá)陽(yáng)性,，溶瘤病毒在腫瘤細(xì)胞內(nèi)復(fù)制到一定的數(shù)量后,，能夠溶解腫瘤細(xì)胞，并能選擇性的殺傷腫瘤細(xì)胞而對(duì)正常細(xì)胞沒(méi)有影響,；感染溶瘤病毒后仍存活的膠質(zhì)瘤干細(xì)胞,，不再具有形成繼發(fā)性細(xì)胞球的能力,，即使加入血清誘導(dǎo)也不再具有貼壁分化的能力；同時(shí),，腫瘤細(xì)胞溶解前48小時(shí),，腫瘤干細(xì)胞還能夠表達(dá)具有生物活性的外源融合基因Endo-Angio蛋白。
盡管該病毒類似的1716,、G207已經(jīng)完成了臨床Ⅰ期試驗(yàn),，并獲得了較為理想的治療效果。但是,，對(duì)于該類病毒經(jīng)基因工程化,，是否具有基因在腫瘤干細(xì)胞的表達(dá)，存有爭(zhēng)議,。該項(xiàng)研究不僅證實(shí)了該類病毒的溶瘤作用,，而且通過(guò)研究證實(shí)了基因工程化的溶瘤病毒具有外源基因的表達(dá)，其療效有望好于1716及G207,，為病毒-基因治療腦惡性膠質(zhì)瘤開(kāi)辟了新的治療途徑,。
劉福生教授認(rèn)為，該種治療方法結(jié)合了溶瘤病毒及基因治療的雙重優(yōu)點(diǎn),，有望成為未來(lái)臨床腦惡性膠質(zhì)瘤的一種新的治療方法,。（生物谷Bioon.com）
生物谷推薦原文出處：
Brain Res. 2011 Apr 12.
Glioma stem cells targeted by oncolytic virus carrying endostatin-angiostatin fusion gene and the expression of its exogenous gene in vitro.
Zhu G, Su W, Jin G, Xu F, Hao S, Guan F, Jia W, Liu F.
Abstract
The development of the cancer stem cell (CSCs) niche theory has provided a new target for the treatment of gliomas. Gene therapy using oncolytic viral vectors has shown great potential for the therapeutic targeting of CSCs. To explore whether a viral vector carrying an exogenous Endo-Angio fusion gene (VAE) can infect and kill glioma stem cells (GSCs), as well as inhibit their vascular niche in vitro, we have collected surgical specimens of human high-grade glioma (world health organization, WHO Classes III-VI) from which we isolated and cultured GSCs under conditions originally designed for the selective expansion of neural stem cells. Our results demonstrate the following: (1) Four lines of GSCs (isolated from 20 surgical specimens) could grow in suspension, were multipotent, had the ability to self-renew and expressed the neural stem cell markers, CD133 and nestin. (2) VAE could infect GSCs and significantly inhibit their viability. (3) The Endo-Angio fusion gene was expressed in GSCs 48h after VAE infection and could inhibit the proliferation of human brain microvascular endothelial cells (HBMEC). (4) Residual viable cells lose the ability of self-renewal and adherent differentiation. In conclusion, VAE can significantly inhibit the activity of GSCs in vitro and the expression of exogenous Endo-Angio fusion gene can inhibit HBMEC proliferation. VAE can be used as a novel virus-gene therapy strategy for glioma.
