Oncolytic effect of Newcastle disease virus is attributed to interferon regulation in canine mammary cancer cell lines

Abstract

Canine mammary carcinoma (CMC) is one of the major health threats in dogs. The oncolytic virotherapy is a promising strategy to treat canine as well as human cancer patients with non‐pathogenic replicating viruses. Here, we evaluated the antitumor activity of one lentogenic, non‐lytic Newcastle disease virus (NDV) LaSota strain expressing GFP (NDV‐GFP) on five different CMCs and one non‐tumorigenic cell line, regarding cell viability, cell death, selectivity index, morphology, global and target gene expression analysis. As evidenced by the selectivity index, all CMC cell lines were more susceptible to NDV‐GFP in comparison with the non‐tumorigenic cells (~3.1× to ~78.7×). In addition, the oncolytic effect of NDV‐GFP was more evident in more malignant CMC cells. Also, we observed an inverse association of the IFN pathway expression and the susceptibility to NDV. The downregulated genes in NDV‐GFP‐sensitive cells were functionally enriched for antiviral mechanisms by interferon and immune system pathways, demonstrating that these mechanisms are the most prominent for oncolysis by NDV. To our knowledge, this is the first description of oncolysis by an NDV strain in canine mammary cancer cells. We also demonstrated specific molecular pathways related to NDV susceptibility in these cancer cells, opening the possibility to use NDV as a therapeutic‐targeted option for more malignant CMCs. Therefore, these results urge for more studies using oncolytic NDVs, especially considering genetic editing to improve efficacy in dogs.

Stemness inhibition by (+)-JQ1 in canine and human mammary cancer cells revealed by machine learning

“…These cell lines were previously classified into mesenchymal-like cells (M5, M25, and CF41.Mg) and epithelial-like cells (E20) with mesenchymallike cells being able to generate tumorspheres in low-adherent plates, while E20 was unable to do so (Xavier et al, 2018). In addition, mesenchymal-like cells' upregulated genes were enriched for important pathways associated with epithelial-mesenchymal transition (EMT), invasiveness, and tumorigenicity (Santos et al, 2021). Based on these previously established phenotypes, our hypothesis was that mesenchymal-like cells would exhibit higher mRNAsi than E20 since several studies report an association between EMT and stemness (Fabregat et al, 2016).…”

Newcastle disease virus LaSota strain induces apoptosis and activates the TNFα/NF‐κB pathway in canine mammary carcinoma cells

“…The canine mammary carcinoma cell line CMT‐U27 (CRL‐3456) was obtained from the American Type Culture Collection (ATCC, Manassas, USA) and maintained in Dulbecco's Modified Eagle Medium/Nutrient Mixture F‐12 (DMEM/F12) (BasalMedia, Shanghai, China) with 10% fetal bovine serum (FBS) (Zeta life, California, USA), penicillin (100 U/mL) and streptomycin (0.1 mg/mL). Madin‐Darby canine kidney cells (MDCK) and African green monkey kidney epithelial cells (Vero cells) were cultured in DMEM and were kind gifts from Dr. Liping Yan (Nanjing Agriculture University) 27,28 . MDCK cells were used as a non‐neoplastic control and Vero cells were used for virus titration.…”

“…Madin-Darby canine kidney cells (MDCK) and African green monkey kidney epithelial cells (Vero cells) were cultured in DMEM and were kind gifts from Dr. Liping Yan (Nanjing Agriculture University). 27,28 MDCK cells were used as a non-neoplastic control and Vero cells were used for virus titration. The cells were incubated at 37 C in a humidified incubator with 5% CO 2 .…”

The gamble between oncolytic virus therapy and IFN

“…Similar to numerous viruses, NDV affects type I IFN ( 145 ). It is well known that type I IFN-mediated PD-L1 expression is an unfavorable factor in tumor treatment.…”