Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Italy
Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy Imperial College of London, London, United Kingdom.
J Virol. 2014 Aug;88(16):9321-34. doi: 10.1128/JVI.00929-14. Epub 2014 Jun 4.
Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3- and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas.
Despite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These results suggest that slightly pathogenic IAVs may prove to be effective for oncolytic virotherapy of PDA and provide grounds for further studies to develop specific and targeted viruses, with the aim of testing their efficacy in clinical contexts.
胰腺导管腺癌（PDA）是人类癌症中最致命的形式，由于晚期诊断和缺乏有效治疗方法，生存率极低。基于观察到禽流感病毒（IAV）在体内对胰腺具有趋向性，本研究旨在测试 IAV 作为杀伤人类 PDA 细胞系的溶瘤剂的疗效。受体特征分析证实，人类 PDA 细胞系分别表达用于禽源和人源 IAV 的α-2,3-和α-2,6 连接聚糖受体。PDA 细胞系对人源和禽源 IAV 分离株的感染敏感，这与这一发现一致。生长动力学实验表明，病毒在 PDA 细胞中的复制比在非转化胰腺导管细胞系中更为优先。最后，在治疗后早期时间点，IAV 感染导致 PDA 细胞中的细胞凋亡水平高于当前 PDA 治疗的基石药物吉西他滨和顺铂。在 BxPC-3 PDA 细胞系中，细胞凋亡是由内在线粒体途径的参与引起的。重要的是，IAV 不会诱导非转化胰腺导管 HPDE6 细胞发生凋亡。使用基于 PDA 细胞系在 SCID 小鼠中的异种移植生长的模型，我们还表明，弱致病性禽源 IAV 经肿瘤内注射后可显著抑制肿瘤生长。总之，这些结果首次表明，IAV 可能有希望成为针对胰腺导管腺癌的溶瘤病毒治疗的未来药物。
尽管进行了密集的研究旨在设计新的治疗方法，但 PDA 仍然是人类癌症中预后最差的。在本研究中，我们提供了第一个证据，表明低致病性禽源 IAV 对人类 PDA 细胞具有趋向性，导致病毒 RNA 复制，并在体外强力诱导细胞凋亡和体内抗肿瘤作用。这些结果表明，弱致病性 IAV 可能对 PDA 的溶瘤病毒治疗有效，并为进一步研究开发特异性和靶向性病毒提供了依据，目的是在临床环境中测试其疗效。
