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.
Highlights
Spontaneous tumours in companion animals are increasingly acknowledged as a suitable model for human cancer [1], in particular for rare neoplastic entities, and provide a unique chance for the development of novel therapeutics [2]
Principal component analysis (PCA) of the normalized data set revealed a clear distinction between the global expression data from the four replicates of infected and non-infected DH82 cells with markedly isolated clusters (Fig. 2)
Viral oncolysis has evolved as a promising treatment strategy for certain forms of malignancies
Summary
Spontaneous tumours in companion animals are increasingly acknowledged as a suitable model for human cancer [1], in particular for rare neoplastic entities, and provide a unique chance for the development of novel therapeutics [2]. Histiocytic sarcoma (HS) represents such a rare disease in human beings, predominantly affecting intestine, skin and soft tissue or occurring systemically [3, 4]. The biological behaviour of HS and the underlying molecular mechanisms have been subject to detailed research infrequently, and an ideal treatment scheme is still lacking [5]. One promising approach for cancer therapy is represented by the use of oncolytic viruses [14]. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
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