對某些惡性腦部腫瘤而言,，即使是很有前景的新藥物也無法達(dá)到治療效果,。最近Heidelberg大學(xué)Wolf Müller等人發(fā)現(xiàn)了產(chǎn)生這種抵抗性的腫瘤標(biāo)記物和分子機(jī)制,。
該課題組發(fā)現(xiàn)某些腦部腫瘤(如星形細(xì)胞瘤)能使細(xì)胞表面的一種關(guān)鍵的蛋白質(zhì)——“死亡受體(death receptor)”去活化。當(dāng)藥物與死亡受體接觸后能引起細(xì)胞死亡,。因此，一個(gè)完整的死亡受體可以作為某種治療手段是否有效的腫瘤標(biāo)記物,。該研究發(fā)表在Clinical Cancer Research雜志上,。
原發(fā)性腦部腫瘤來源于腦部細(xì)胞，尤其是惡性膠質(zhì)母細(xì)胞瘤突變體,。盡管對膠質(zhì)母細(xì)胞瘤患者采取各種治療手段，但患者一般在診斷出該腫瘤后兩年內(nèi)死亡,。
研究人員對不同的腦部腫瘤(如星形細(xì)胞瘤)進(jìn)行研究,，發(fā)現(xiàn)當(dāng)死亡受體DR4的基因發(fā)生“啟動子甲基化”時(shí)，超過75%的該基因都會關(guān)閉,。這說明基因片段中甲基化群的積累對該基因的表達(dá)很重要,。
死亡受體DR4對開發(fā)受體特異性療法(receptor-specific therapy)是一個(gè)值得引起人注意的靶標(biāo),。目前已有已開發(fā)出來一種名為Mapatumumab的抗體蛋白,，能夠直接與死亡受體結(jié)合并引發(fā)細(xì)胞死亡。該藥物目前正在進(jìn)行臨床階段的測試來治療肺癌,。（生物谷Bioon.com）
生物谷推薦原始出處：
Clinical Cancer Research 15, 5457, September 1, 2009. doi: 10.1158/1078-0432.CCR-09-1125
Epigenetic Silencing of Death Receptor 4 Mediates Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Resistance in Gliomas
Agnes Elias1, Markus D. Siegelin1, Albert Steinmüller1, Andreas von Deimling1,2, Ulrike Lass2, Bernhard Korn3 and Wolf Mueller1
Authors' Affiliations: 1 Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universit?t Heidelberg; 2 Clinical Cooperation Unit Neuropathology G380 and 3 Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany
Purpose: To identify and characterize epigenetically regulated genes able to predict sensitivity or resistance to currently tested chemotherapeutic agents in glioma therapy.
Experimental Design: We used methylation-sensitive BeadArray technology to identify novel epigenetically regulated genes associated with apoptosis and with potential therapeutic targets in glioma therapy. To elucidate the functional consequences of promoter methylation in the identified target death receptor 4 (DR4), we investigated tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated and anti-DR4–mediated apoptosis in glioma cell lines (U373 and A172) with loss of DR4 and one glioma cell line (LN18) with robust DR4 expression.
Results: In human astrocytic tumors, we detected DR4 promoter hypermethylation in 60% (n = 5) of diffuse astrocytomas WHO grade 2, in 75% (n = 8) of anaplastic astrocytomas WHO grade 3, and in 70% of glioblastomas WHO grade 4 (n = 33). DR4 is a cell surface protein restricted to glioma cells and is targeted by TRAIL. Glioma cell lines U373 and A172 harbored heavily methylated DR4 promoters, and 5-aza-2-deoxycytidine–mediated demethylation reconstituted DR4 expression in these cell lines. Functional knockdown of DR4 by DR4-specific small interfering RNA in TRAIL-sensitive glioma cell line LN18 significantly mitigated apoptosis induced by an agonistic anti-DR4 antibody. 5-Aza-2-deoxycytidine–mediated demethylation resulted in a functional reconstitution of DR4 on the cell surface of TRAIL-resistant glioma cell line U373 and sensitized U373 to TRAIL-mediated apoptosis. Suppression of DR4 by small interfering RNA in demethylated U373 successfully reestablished the TRAIL-resistant phenotype of U373.
Conclusions: DR4 promoter methylation is frequent in human astrocytic gliomas, and epigenetic silencing of DR4 mediates resistance to TRAIL/DR4-based glioma therapies.
