Guiho Romain, Biteau Kevin, Grisendi Giulia, Taurelle Julien, Chatelais Mathias, Gantier Malika, Heymann Dominique, Dominici Massimo, Redini Françoise
INSERM, UMR-957, Equipe labellisée LIGUE contre le CANCER 2012, Nantes, F-44035, France.
Université de Nantes, EA 3822, Faculté de Médecine, Laboratoire de Physiopathologie de la Résorption Osseuse et thérapie des tumeurs osseuses primitives, Nantes, F-44035, France.
Int J Cancer. 2016 Dec 15;139(12):2802-2811. doi: 10.1002/ijc.30402. Epub 2016 Sep 12.
Ewing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL-induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full-length human TRAIL were co-cultured with several human EWS cell lines, inducing apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. In vivo, TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell-based delivery of a potent apoptosis-inducing factor could be relevant in EWS.
尤因肉瘤（EWS）是第二常见的儿童恶性骨肿瘤。在过去30年里，EWS患者未见任何重大治疗进展，尤其是转移性疾病患者，这需要新的治疗策略。促凋亡细胞因子肿瘤坏死因子相关凋亡诱导配体（TRAIL）可选择性杀死肿瘤细胞，同时不损伤正常细胞，使其成为多种癌症中一种有前景的治疗工具。然而，某些EWS细胞系似乎对重组人（rh）TRAIL诱导的凋亡具有抗性。因此，我们推测载体细胞表面呈现TRAIL可能会克服这种抗性并引发凋亡。为此，将稳定转染以表达全长人TRAIL的人脂肪间充质基质/干细胞（MSC）与几种人EWS细胞系共培养，即使在最初对rhTRAIL或死亡受体DR5的抗体激动剂AMG655耐药的细胞系中，也能通过细胞间接触诱导凋亡。在体内，MSC递送的TRAIL能够在尤因肉瘤的两种原位模型中对抗肿瘤进展，这与半胱天冬酶激活相关，表明基于细胞递送有效的凋亡诱导因子在EWS中可能具有重要意义。
