Viral oncolysis - can insights from measles be transferred to canine distemper virus?

Abstract

Neoplastic diseases represent one of the most common causes of death among humans and animals. Currently available and applied therapeutic options often remain insufficient and unsatisfactory, therefore new and innovative strategies and approaches are highly needed. Periodically, oncolytic viruses have been in the center of interest since the first anecdotal description of their potential usefulness as an anti-tumor treatment concept. Though first reports referred to an incidental measles virus infection causing tumor regression in a patient suffering from lymphoma several decades ago, no final treatment concept has been developed since then. However, numerous viruses, such as herpes-, adeno- and paramyxoviruses, have been investigated, characterized, and modified with the aim to generate a new anti-cancer treatment option. Among the different viruses, measles virus still represents a highly interesting candidate for such an approach. Numerous different tumors of humans including malignant lymphoma, lung and colorectal adenocarcinoma, mesothelioma, and ovarian cancer, have been studied in vitro and in vivo as potential targets. Moreover, several concepts using different virus preparations are now in clinical trials in humans and may proceed to a new treatment option. Surprisingly, only few studies have investigated viral oncolysis in veterinary medicine. The close relationship between measles virus (MV) and canine distemper virus (CDV), both are morbilliviruses, and the fact that numerous tumors in dogs exhibit similarities to their human counterpart, indicates that both the virus and species dog represent a highly interesting translational model for future research in viral oncolysis. Several recent studies support such an assumption. It is therefore the aim of the present communication to outline the mechanisms of morbillivirus-mediated oncolysis and to stimulate further research in this potentially expanding field of viral oncolysis in a highly suitable translational animal model for the benefit of humans and dogs.

Figure 1

Potential mechanisms leading to tumor cell destruction upon infection with an oncolytic virus. (A) Binding to frequently overexpressed virus receptors initiates internalization of the virus into the tumor cell. Viral nucleic acid is released and transcribed which leads to cellular antiviral defense mechanisms such as apoptosis [23,24,25] (a). Upon viral gene expression viral proteins are produced exploiting the cellular machinery. Virions are formed by assembly of viral proteins and replication of viral nucleic acids. Tumor cells may subsequently be lysed by massive budding of virions from the cell surface [26] (b). (B) Pathogen associated molecular pattern (PAMP, viral nucleic acids, viral proteins) stimulate production of antiviral cytokines (IFN, IL-1, IL-6, IL-12, TNF) which in turn lead to attraction of immune cells mediating cytotoxicity and phagocytosis (c). IFN-γ polarizes macrophages towards the M1-phenotype [32,33] fostering accumulation of M1‑macrophage derived cytotoxic factors (nitrogen monoxide, inducible nitric oxide synthase, reactive oxygen species) and proinflammatory/angiostatic cytokines (IL-12, TNF) in the tumor microenvironment that may support antitumor treatment [30,31] (d). MHC-I mediated presentation of viral proteins activates CD8⁺ cytotoxic T cells, triggering lysis of the oncolytic virus-infected tumor cell (e). (C) PAMP-enhanced secretion of IFN-γ and IL-12 by the oncolytic virus-infected tumor cell may initiate the complex interplay between IFN-γ, IL-12, NK-cells and IP-10 to eventually limit tumor angiogenesis [34,35,36,37,38] (f). IL-12 derived from M1-macrophages may contribute to this process (g). Moreover the externalization of the N-terminal fragment of the ER-chaperone protein calreticulin (vasostatin) may be involved in the confinement of tumor vascularization [35,39,40,41] (h). CD, cluster of differentiation; ER, endoplasmic reticulum; IFN, interferon; IFN-γ, interferon-gamma; IL, interleukin; IP-10, IFN-γ-inducible protein-10; MHC, major histocompatibility complex; M1, macrophage 1 phenotype; TNF, tumor necrosis factor.

Figure 2

Different types of oncolytic measles virus. (A) The H-protein of this live-attenuated naturally tumor selective Edmonston B-strain binds to CD46, a surface receptor frequently overexpressed by tumor cells. Thus, a tumor cell-specific infection with oncolytic MV is facilitated [47,49,50]. (B) By genetically fusing a single chain variable fragment directed against CD133 to the H-protein, this measles virus is tumor selectivity-enhanced. It selectively infects CD133-expressing tumor initiating cells, thus, supporting antiproliferative therapies [51]. Tumor initiating cells/cancer stem cells are believed to be a source of recurrent tumor growth after initial antitumor therapy [52]. (C) By insertion of cDNA for the human thyroidal sodium iodide symporter (NIS) as an additional transcription unit downstream of the viral hemagglutinin gene, this efficacy-enhanced measles virus leads to expression of NIS by the infected tumor cell [53]. NIS is able to concentrate simultaneously given radioiodine isotopes at the site of tumor implantation, enhancing the radiotherapeutic effect [54]. CD, cluster of differentiation; MV, measles virus; MV F-glycoprotein, measles virus fusion glycoprotein; MV H-glycoprotein, measles virus hemagglutinin glycoprotein; MV M-protein, measles virus matrix protein; NIS, thyroidal sodium iodide symporter; scFv, single chain variable fragment.