Ucur E, Mattern J, Wenger T, Okouoyo S, Schroth A, Debatin K-M, Herr I
Clinical Cooperation Unit, Molecular Oncology/Pediatrics, German Cancer Research Center, Heidelberg, Germany.
Br J Cancer. 2003 Dec 1;89(11):2155-62. doi: 10.1038/sj.bjc.6601407.
In the present study, we demonstrate the utility of a non-tumour-forming T-cell line for the inducible gene transfer of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), which has been shown to selectively induce apoptosis in malignant but not in normal cells. To generate T cells inducible for TRAIL expression, we stably transfected Jurkat cells with TRAIL in the context of the Tet-On system. The switched on cells strongly expressed TRAIL mRNA, whose protein product was expressed on the cell surface. Paracrine induction of apoptosis in human target tumour cells was solely found for membrane-bound TRAIL. The Jurkat-TRAIL cells itself survived due to clonal selection of TRAIL-resistant cells. Jurkat-TRAIL cells had an additive effect with cytotoxic drugs in vitro, since cell death was enhanced. To elucidate the antitumoral activity of these Jurkat-TRAIL cells in vivo, we injected them intratumorally in xenografts of human Burkitt lymphomas. Switching on expression of TRAIL by adding tetracycline to the drinking water of the mice strongly reduced tumour growth by apoptosis in a caspase-dependent manner. Thus, non-tumour-forming T-cell lines offer a novel method for gene transfer and inducible expression of TRAIL in tumour therapy.
在本研究中，我们证明了一种非致瘤性T细胞系在肿瘤坏死因子（TNF）相关凋亡诱导配体（Apo2L/TRAIL）诱导基因转移中的效用，该配体已被证明能选择性地诱导恶性细胞而非正常细胞凋亡。为了产生可诱导TRAIL表达的T细胞，我们在Tet-On系统中用TRAIL稳定转染了Jurkat细胞。开启的细胞强烈表达TRAIL mRNA，其蛋白产物在细胞表面表达。仅在膜结合的TRAIL中发现了对人靶肿瘤细胞凋亡的旁分泌诱导作用。Jurkat-TRAIL细胞自身由于对TRAIL耐药的细胞的克隆选择而存活。Jurkat-TRAIL细胞在体外与细胞毒性药物具有相加作用，因为细胞死亡增加。为了阐明这些Jurkat-TRAIL细胞在体内的抗肿瘤活性，我们将它们瘤内注射到人伯基特淋巴瘤的异种移植瘤中。通过向小鼠饮用水中添加四环素开启TRAIL的表达，以半胱天冬酶依赖性方式通过凋亡强烈降低肿瘤生长。因此，非致瘤性T细胞系为肿瘤治疗中TRAIL的基因转移和诱导表达提供了一种新方法。
