title: Oncolytic activity of avian influenza virus in human pancreatic ductal adenocarcinoma cell lines.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Italy skasloff@izsvenezie.it.
authors.forename: Samantha B
authors.initials: SB
authors.lastname: Kasloff
authors.affiliation: Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy Imperial College of London, London, United Kingdom.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Pizzuto
authors.affiliation: Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Silic-Benussi
authors.affiliation: Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pavone
authors.affiliation: Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ciminale
authors.affiliation: Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Capua
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001717:Birds; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D009980:Influenza A virus / Q000378:metabolism*; D005585:Influenza in Birds; D015552:Injections, Intralesional / Q000379:methods; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays