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Development of new therapy for canine mammary cancer with recombinant measles virus.

ABSTRACT: Oncolytic virotherapy is a promising treatment strategy for cancer. We previously generated a recombinant measles virus (rMV-SLAMblind) that selectively uses a poliovirus receptor-related 4 (PVRL4/Nectin4) receptor, but not signaling lymphocyte activation molecule (SLAM). We demonstrated that the virus exerts therapeutic effects against human breast cancer cells. Here, we examined the applicability of rMV-SLAMblind to treating canine mammary cancers (CMCs). We found that the susceptibilities of host cells to rMV-SLAMblind were dependent on canine Nectin-4 expression. Nectin-4 was detected in four of nine CMC cell lines. The rMV-SLAMblind efficiently infected those four Nectin-4-positive cell lines and was cytotoxic for three of them (CF33, CHMm, and CTBm). In vivo experiment showed that the administration of rMV-SLAMblind greatly suppressed the progression of tumors in mice xenografted with a CMC cell line (CF33). Immunohistochemistry revealed that canine Nectin-4 was expressed in 45% of canine mammary tumors, and the tumor cells derived from one clinical specimen were efficiently infected with rMV-SLAMblind. These results suggest that rMV-SLAMblind infects CMC cells and displays antitumor activity in vitro, in xenografts, and ex vivo. Therefore, oncolytic virotherapy with rMV-SLAMblind can be a novel method for treating CMCs.

SUBMITTER: Shoji K

PROVIDER: S-EPMC4782952 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Project description:Canine distemper (CD) is a highly contagious viral disease worldwide. Although live attenuated vaccine is available as a preventive measure against the disease, cases of vaccination failure highlight the importance of potential alternative agent against canine distemper virus (CDV). CDV infects cells mainly by binding signaling lymphocyte activation molecule (SLAM) and Nectin-4 receptor. Here, to develop a new and safe antiviral biological agent for CD, we constructed and expressed CDV receptor proteins fused with Fc region of canine IgG-B, namely, SLAM-Fc, Nectin-Fc and SLAM-Nectin-Fc in HEK293T cells, and antiviral activity of these receptor-Fc proteins was subsequently evaluated. The results showed that the receptor-Fc proteins efficiently bound to receptor binding domain (RBD) of CDV-H, meanwhile, these receptor-Fc proteins competitively inhibited the binding of His-tagged receptor proteins (SLAM-His or Nectin-His) to CDV-H-RBD-Flag protein. Importantly, receptor-Fc proteins exhibited potent anti-CDV activity in vitro. Treatment with receptor-Fc proteins at the pre-entry stage dramatically suppressed CDV infectivity in Vero cells stably expressing canine SLAM. The minimum effective concentration (MEC) of SLAM-Fc, Nectin-Fc and SLAM-Nectin-Fc was 0.2 μg/mL, 0.2 μg/mL, 0.02 μg/mL. The 50% inhibition concentration (IC50) of three proteins was 0.58 μg/mL, 0.32 μg/mL and 0.18 μg/mL, respectively. Moreover, treatment with receptor-Fc proteins post viral infection can also inhibit CDV reproduction, the MEC of SLAM-Fc, Nectin-Fc and SLAM-Nectin-Fc was same as pre-treatment, and the IC50 of receptor-Fc proteins was 1.10 μg/mL, 0.99 μg/mL and 0.32 μg/mL, respectively. The results suggested that the receptor-Fc proteins were more effective for pre-entry treatment than post-infection treatment, furthermore, SLAM-Nectin-Fc was more effective than SLAM-Fc and Nectin-Fc. These findings revealed the receptor-Fc proteins were promising candidates as inhibitor against CDV.

Project description:Research using in vitro canine mammary cancer cell lines and naturally-occurring canine mammary tumors are not only fundamental models used to advance the understanding of cancer in veterinary patients, but are also regarded as excellent translational models of human breast cancer. Human breast cancer is commonly treated with radiotherapy; however, tumor response depends on both innate radiosensitivity and on tumor repopulation by cells that develop radioresistance. Comparative canine and human studies investigating the mechanisms of radioresistance may lead to novel cancer treatments that benefit both species. In this study, we developed a canine mammary cancer (REM-134) radioresistant (RR) cell line and investigated the cellular mechanisms related to the development of acquired radioresistance. We performed a comparative analysis of this resistant model with our previously developed human breast cancer radioresistant cell lines (MCF-7 RR, ZR-751 RR, and MDA-MB-231 RR), characterizing inherent differences through genetic, molecular, and cell biology approaches. RR cells demonstrated enhanced invasion/migration capabilities, with phenotypic evidence suggestive of epithelial-to-mesenchymal transition. Similarities were identified between the REM-134 RR, MCF-7 RR, and ZR-751 RR cell lines in relation to the pattern of expression of both epithelial and mesenchymal genes, in addition to WNT, PI3K, and MAPK pathway activation. Following the development of radioresistance, transcriptomic data indicated that parental MCF-7 and ZR-751 cell lines changed from a luminal A classification to basal/HER2-overexpressing (MCF-7 RR) and normal-like/HER2-overexpressing (ZR-751 RR). These radioresistant subtypes were similar to the REM-134 and REM-134 RR cell lines, which were classified as HER2-overexpressing. To our knowledge, our study is the first to generate a canine mammary cancer RR cell line model and provide a comparative genetic and phenotypic analysis of the mechanisms of acquired radioresistance between canine and human cancer cell lines. We demonstrate that the cellular processes that occur with the development of acquired radioresistance are similar between the human and canine cell lines; our results therefore suggest that the canine model is appropriate to study both human and canine radioresistant mammary cancers, and that treatment strategies used in human medicine may also be applicable to veterinary patients.

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Development of new therapy for canine mammary cancer with recombinant measles virus.

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