title: Reduced angiogenic gene expression in morbillivirus-triggered oncolysis in a translational model for histiocytic sarcoma.
abstract: Histiocytic sarcoma represents a rare malignant tumour with a short survival time, indicating the need of novel treatment strategies including oncolytic virotherapy. The underlying molecular mechanisms of viral oncolysis are largely unknown. As cancer in companion animals shares striking similarities with human counterparts, we chose a permanent canine histiocytic sarcoma cell line (DH82 cells) to identify global transcriptome changes following infection with canine distemper virus (CDV), a paramyxovirus closely related to human measles virus. Microarray analysis identified 3054 differentially expressed probe sets (DEPs), encoding for 892 up- and 869 down-regulated unique canine genes, respectively, in DH82 cells persistently infected with the vaccine strain Onderstepoort of CDV (DH82-Ond-pi), compared to non-infected DH82 cells. Up-regulated genes were predominantly related to immune processes, as demonstrated by functional enrichment analysis. Moreover, there was substantial enrichment of genes characteristic for classically activated M1 and alternatively activated M2 macrophages in DH82-Ond-pi; however, significant polarization into either of both categories was lacking. 'Angiogenesis' was the dominant enriched functional term for the down-regulated genes, highlighting decreased blood vessel generation as a potential mechanism of paramyxovirus-induced oncolysis in DH82 cells. The anti-angiogenic effect of infection was verified by immunohistochemistry, which revealed a lower blood vessel density in an in vivo mouse model, xenotransplanted with DH82-Ond-pi, compared to mice transplanted with non-infected DH82 cells. Reduction in angiogenesis appears to be an important oncolytic mechanism of CDV in DH82 cells, suggesting that similar mechanisms might account for human histiocytic sarcoma and maybe other tumours in conjunction with measles virus.
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Vanessa Maria
authors.initials: VM
authors.lastname: Pfankuche
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Spitzbarth
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lapp
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Ulrich
authors.affiliation: Department of Non-Clinical Drug Safety, Boehringer Ingelheim Pharma GmbH&Co KG, Biberach (Riß), Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Deschl
authors.affiliation: Department of Non-Clinical Drug Safety, Boehringer Ingelheim Pharma GmbH&Co KG, Biberach (Riß), Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Kalkuhl
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Puff
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004217:Distemper Virus, Canine; D004285:Dogs; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D054747:Histiocytic Sarcoma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D007109:Immunity / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D058977:Molecular Sequence Annotation; D018103:Morbillivirus / Q000502:physiology*; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D050130:Oncolytic Virotherapy; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D025341:Principal Component Analysis; D012074:Remission Induction; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D057170:Translational Research, Biomedical; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1
keywords: DH82; canine distemper virus; histiocytic sarcoma; macrophage polarization; microarray; oncolysis