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.

Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro

“…Canine distemper virus represents a Morbillivirus closely related to human measles virus [9], with the latter already described as a promising oncolytic virus in human medicine that has reached the phase of clinical trials [10]. Similarly, the attenuated Onderstepoort vaccine strain of canine distemper virus (CDV-Ond) represents a potential oncolytic virus for the treatment of canine histiocytic sarcomas [11,12].…”

Oncolytic activity of canine distemper virus in canine mammary tubular adenocarcinoma cells

“…Previously studies have reported that CDV induces apoptosis in many cancer cell lines, including canine neoplastic lymphocytes, canine adenofibrosarcoma cells, human breast cancer cells and human cervical cancer cells . Persistent infection by CDV exhibited anti‐angiogenic properties in a canine histiocytic cell line . These capacities suggest that it may find a practical use in oncolytic gene therapy .…”

“…[16][17][18] Persistent infection by CDV exhibited anti-angiogenic properties in a canine histiocytic cell line. 19 These capacities suggest that it may find a practical use in oncolytic gene therapy. 20 However, compared to oncolytic MV, the oncolytic potential of CDV in canine mammary carcinoma (CMC) has received only limited attention and the underlying oncolytic mechanisms of CDV remained to be elucidated.…”

Anti‐tumour activity of oncolytic reovirus against canine histiocytic sarcoma cells

“…To our knowledge, there are few reports about the effects of oncolytic viruses (morbillivirus and ECHO‐7 virus) on canine and human histiocytic sarcoma . Therefore, data on the oncolytic effects of reovirus on histiocytic sarcoma cells are expected to serve as important evidences for the rational use of oncolytic viruses in clinical trials.…”

“…To our knowledge, there are few reports about the effects of oncolytic viruses (morbillivirus and ECHO-7 virus) on canine and human histiocytic sarcoma. [17][18][19] Therefore, data on the oncolytic effects of reovirus on histiocytic sarcoma cells are expected to serve as important evidences for the rational use of oncolytic viruses in clinical trials. In the present study, we examined the oncolytic effects, both in vitro and in vivo, of reovirus on canine histiocytic sarcoma cell lines and on normal DCs derived from healthy dogs.…”