Influence of canine distemper virus on mesenchymal to epithelial transition in canine histiocytic sarcoma cells

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.

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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

Viruses ◽

10.3390/v12020200 ◽

2020 ◽

Vol 12 (2) ◽

pp. 200 ◽

Cited By ~ 4

Author(s):

Federico Armando ◽

Matteo Gambini ◽

Attilio Corradi ◽

Chiara Giudice ◽

Vanessa Maria Pfankuche ◽

...

Keyword(s):

Oxidative Stress ◽

Data Analysis ◽

Microarray Data ◽

Canine Distemper Virus ◽

Histiocytic Sarcoma ◽

Microarray Data Analysis ◽

Canine Distemper ◽

The Impact ◽

Dh82 Cells

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.

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Drivers of canine distemper virus exposure in dogs at a wildlife interface in Janos, Mexico

Veterinary Record Open ◽

10.1002/vro2.7 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Rocío Almuna ◽

Andrés M. López‐Pérez ◽

Rosa E. Sarmiento ◽

Gerardo Suzán

Keyword(s):

Canine Distemper Virus ◽

Canine Distemper ◽

Virus Exposure

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Antiviral Screen against Canine Distemper Virus-Induced Membrane Fusion Activity

Viruses ◽

10.3390/v13010128 ◽

2021 ◽

Vol 13 (1) ◽

pp. 128

Author(s):

Neeta Shrestha ◽

Flavio M. Gall ◽

Jonathan Vesin ◽

Marc Chambon ◽

Gerardo Turcatti ◽

...

Keyword(s):

Membrane Fusion ◽

Small Molecule ◽

High Throughput Screening ◽

Measles Virus ◽

Canine Distemper Virus ◽

Rna Virus ◽

Preventive Measure ◽

Close Relative ◽

Fusion Activity ◽

Canine Distemper

Canine distemper virus (CDV), a close relative of the human pathogen measles virus (MeV), is an enveloped, negative sense RNA virus that belongs to the genus Morbillivirus and causes severe diseases in dogs and other carnivores. Although the vaccination is available as a preventive measure against the disease, the occasional vaccination failure highlights the importance of therapeutic alternatives such as antivirals against CDV. The morbilliviral cell entry system relies on two interacting envelope glycoproteins: the attachment (H) and fusion (F) proteins. Here, to potentially discover novel entry inhibitors targeting CDV H, F and/or the cognate receptor: signaling lymphocyte activation molecule (SLAM) proteins, we designed a quantitative cell-based fusion assay that matched high-throughput screening (HTS) settings. By screening two libraries of small molecule compounds, we successfully identified two membrane fusion inhibitors (F2736-3056 and F2261-0043). Although both inhibitors exhibited similarities in structure and potency with the small molecule compound 3G (an AS-48 class morbilliviral F-protein inhibitor), F2736-3056 displayed improved efficacy in blocking fusion activity when a 3G-escape variant was employed. Altogether, we present a cell-based fusion assay that can be utilized not only to discover antiviral agents against CDV but also to dissect the mechanism of morbilliviral-mediated cell-binding and cell-to-cell fusion activity.

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