Abstract
Histiocytic sarcomas represent malignant tumors which require new treatment strategies. Canine distemper virus (CDV) is a promising candidate due to its oncolytic features reported in a canine histiocytic sarcoma cell line (DH82 cells). Interestingly, the underlying mechanism might include a dysregulation of angiogenesis. Based on these findings, the aim of the present study was to investigate the impact of a persistent CDV-infection on oxidative stress mediated changes in the expression of hypoxia-inducible factor (HIF)-1α and its angiogenic downstream pathway in DH82 cells in vitro. Microarray data analysis, immunofluorescence for 8-hydroxyguanosine, superoxide dismutase 2 and catalase, and flow cytometry for oxidative burst displayed an increased oxidative stress in persistently CDV-infected DH82 cells (DH82Ond pi) compared to controls. The HIF-1α expression in DH82Ond pi increased, as demonstrated by Western blot, and showed an unexpected, often sub-membranous distribution, as shown by immunofluorescence and immunoelectron microscopy. Furthermore, microarray data analysis and immunofluorescence confirmed a reduced expression of VEGF-B in DH82Ond pi compared to controls. In summary, these results suggest a reduced activation of the HIF-1α angiogenic downstream pathway in DH82Ond pi cells in vitro, most likely due to an excessive, unusually localized, and non-functional expression of HIF-1α triggered by a CDV-induced increased oxidative stress.
Highlights
Neoplastic diseases are one of the major causes of death in humans and domestic animals due to disappointing results of many conventional therapies [1,2]
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]
Non-infected DH82 cells obtained from the European Collection of Authenticated Cell Cultures (ECACC No 94062922), and DH82 cells persistently infected with canine distemper virus (CDV)-Ond (DH82Ond pi) that were established as formerly described [20], were cultured according to standard procedures as previously reported [11]
Summary
Neoplastic diseases are one of the major causes of death in humans and domestic animals due to disappointing results of many conventional therapies [1,2]. Acute infection of DH82 cells with CDV-Ond in vitro resulted in a prominent cell death at 12 days post infection [12], followed by establishment of persistent infection in tumor cells surviving the acute lytic phase [11]. In this context, subcutaneous xenotransplantion of persistently CDV-Ond infected DH82 cells resulted in a total regression of neoplasms in a mouse model [11]. Additional investigations using persistently CDV-infected DH82 cells might represent a promising model to study virus-induced alterations of cancer hallmarks [22]
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